The effect of beta-glucan on wound healing: a systematic review and meta-analysis

Introduction: Vacuum therapy is a new concept in wound treatment. Animal studies have shown good results in chronic and acute wounds. In clinical practice we have used the system for many wounds with very promising results. However there are few randomized clinical trials that prove the efficacy of the system. Patients and methods: In 2002 we have started a randomized prospective clinical trial to compare the results of Vacuum Assisted Closure versus our wound management protocol with mainly foam dressings and alginates. In this study we have included acute and chronic wounds. The wounds were assessed 3 times a week by 3 researchers (a medical doctor and 2 nurses). We looked at the wound healing, described in terms of color, smell, temperature and aspect of the wound. The size and depth of the wound was recorded and photographs were taken. Once a week we did a swab of the wound. Besides the effect on wound healing we also looked at the time that was needed for dressing changes, the benefits for the patient and the nurses and the costs of the therapy. Results: At this moment we have treated 35 patients. The preliminary results will be presented at the meeting.With this study as an example we will also illustrate some of the problems that can be encountered when designing a clinical trial in wound healing.

The adverse impact of chronic wounds is felt worldwide. The concerns for advanced wound care product are progressively increasing due to factors such as value for money spent in wound care products. Acute and Chronic wounds are managed in most health facilities in Ghana with sodium chloride (0.9%) infusion solution and povidone iodine fortified with metronidazole solution. The procedure is usually done by the nurse cleaning the wound with the saline solution wet gauze or cotton and then covered with the povidone iodine wet gauze for acute and chronic wounds. For chronic infected wounds, the wound is usually cleaned with saline solution and covered with wet gauze saline or currently with neomycin wound care spray or powdered antibiotics applied on the wounds. But it is popular as many wounds are covered with povidone iodine after wound cleaning in wound care practices in Ghana. Despite all these efforts, many wounds, especially chronic type wounds take a very long time to heal or sometimes fails to heal which reduce the quality of life of the people suffering from the menace. When it happens in this way, many resort to the use of local remedies to cause the wounds to heal but no avail, especially in Ghana where advanced treatment is scare. It is against this background that focal research in wound care was done in Ghana to come out with an innovative pharmaceutical wound care product effective for chronic and acute wounds healing to improve the quality of life of people as global burden of wounds escalates. In a Blind Observational Study for a period of five years in Ghana to observe the wound care products efficacy to heal wounds especially chronic types, the objective of the study was to examine a new product efficacy in chronic wound healing in the targeted population of patients with wounds. A product that has dual purpose of wound care as a cleaning and application agent, also has unique product pharmaceutical characteristics. A scalable, easy- to- use, multi-purpose, multi-use and cost-effective product, able to address the barriers or problems of wounds healing. The areas of consideration as far as wound care are concerned included: The study also sought to observe the product ability to control wound pains, control wound bleeding, control and prevent wound infection, remove wound debris, remove wound exudates effecting wounds healing at reduced healing time and with minimal scar in varied targeted patients’ population. Again, to observe the product with outcome of which to mitigate the long-term effect of chronic wounds like recurrent hospitalizations, financial burden, amputations, deformity, and frequent visit to hospital for wound care. One product, 9G Wound Solution (a cleaning and application product) manufactured by Pat J Health Company Limited, Ghana, was effective in wounds healing, especially, effective chronic wounds healing. The product was used to subject varied patients’ population with wounds on randomized basis, for wound care, and through observation the direct short, intermedial and long-term outcomes recorded of product effectiveness recorded. The outcome reported included control of wound pains, control of wound odor, control of bleeding, control of wound infection, removal of wounds exudates, removal of wound debris and ultimately reduced wound healing time to prevent wounds complications like amputations. The study was progressively extended across 10 regions in Ghana to cover 500 patient population with varied wounds. Patients’ population included those with Diabetic ulcers, Burns, pressure ulcers, venous ulcers, herpes zoster skin ulcers, Perineum wounds, Surgical abdomen-pelvic wounds, Traumatic wounds, Buruli Ulcers, gas gangrene wounds, and Mouth ulcers. The outcome of using the new wound care product were directly observed for the study period. By this observational study, the new product was observed to be superior to the controls as this product was able to heal 99% patients who had wounds, especially chronic wounds for many years, including 20years-old wound at reduced healing rate with no reoccurrence within the study period. The product scientifically readily released to the wound environment modulators capable to address the problems or barriers of wounds and simultaneously promoting modulators effective for wound healing. The product was not only effective in chronic wound healing at reduced time but also controlled wound pains shortly, controlled wound odor shortly, stopped wound bleeding, fought and controlled wound infection. However, using the product needed change of wound dressing every two days. The long-term effect of the product on target population not conclusively observed within the period of the research. We need to continuously observe the reported long-term effect of the product efficacy.

Ectopic localization of matrix metalloproteinase-9 in chronic cutaneous wounds

Aloe vera is a cactus-like perennial succulent belonging to the Liliaceae Family that is commonly grown in tropical climates. Animal studies have suggested that Aloe vera may help accelerate the wound healing process. To determine the effects of Aloe vera-derived products (for example dressings and topical gels) on the healing of acute wounds (for example lacerations, surgical incisions and burns) and chronic wounds (for example infected wounds, arterial and venous ulcers). We searched the Cochrane Wounds Group Specialised Register (9 September 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), Ovid MEDLINE (2005 to August Week 5 2011), Ovid MEDLINE (In-Process & Other Non-Indexed Citations 8 September 2011), Ovid EMBASE (2007 to 2010 Week 35), Ovid AMED (1985 to September 2011) and EBSCO CINAHL (1982 to 9 September 2011). We did not apply date or language restrictions. We included all randomised controlled trials that evaluated the effectiveness of Aloe vera, aloe-derived products and a combination of Aloe vera and other dressings as a treatment for acute or chronic wounds. There was no restriction in terms of source, date of publication or language. An objective measure of wound healing (either proportion of completely healed wounds or time to complete healing) was the primary endpoint. Two review authors independently carried out trial selection, data extraction and risk of bias assessment, checked by a third review author. Seven trials were eligible for inclusion, comprising a total of 347 participants. Five trials in people with acute wounds evaluated the effects of Aloe vera on burns, haemorrhoidectomy patients and skin biopsies. Aloe vera mucilage did not increase burn healing compared with silver sulfadiazine (risk ratio (RR) 1.41, 95% confidence interval (CI) 0.70 to 2.85). A reduction in healing time with Aloe vera was noted after haemorrhoidectomy (RR 16.33 days, 95% CI 3.46 to 77.15) and there was no difference in the proportion of patients completely healed at follow up after skin biopsies. In people with chronic wounds, one trial found no statistically significant difference in pressure ulcer healing with Aloe vera (RR 0.10, 95% CI -1.59 to 1.79) and in a trial of surgical wounds healing by secondary intention Aloe vera significantly delayed healing (mean difference 30 days, 95% CI 7.59 to 52.41). Clinical heterogeneity precluded meta-analysis. The poor quality of the included trials indicates that the trial results must be viewed with extreme caution as they have a high risk of bias. There is currently an absence of high quality clinical trial evidence to support the use of Aloe vera topical agents or Aloe vera dressings as treatments for acute and chronic wounds.

BACKGROUND: Aloe vera is a cactus-like perennial succulent belonging to the Liliaceae Family that is commonly grown in tropical climates. Animal studies have suggested that Aloe vera may help accelerate the wound healing process. OBJECTIVE: To determine the effects of Aloe vera-derived products (for example dressings and topical gels) on the healing of acute wounds (for example lacerations, surgical incisions and burns) and chronic wounds (for example infected wounds, arterial and venous ulcers). METHODS:Search methods: We searched the Cochrane Wounds Group Specialised Register (9 September 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), Ovid MEDLINE (2005 to August Week 5 2011), Ovid MEDLINE (In-Process & Other Non-Indexed Citations 8 September 2011), Ovid EMBASE (2007 to 2010 Week 35), Ovid AMED (1985 to September 2011) and EBSCO CINAHL (1982 to 9 September 2011). We did not apply date or language restrictions. Selection criteria: We included all randomised controlled trials that evaluated the effectiveness of Aloe vera, aloe-derived products and a combination of Aloe vera and other dressings as a treatment for acute or chronic wounds. There was no restriction in terms of source, date of publication or language. An objective measure of wound healing (either proportion of completely healed wounds or time to complete healing) was the primary endpoint. Data collection and analysis: Two review authors independently carried out trial selection, data extraction and risk of bias assessment, checked by a third review author. MAIN RESULTS: Seven trials were eligible for inclusion, comprising a total of 347 participants. Five trials in people with acute wounds evaluated the effects of Aloe vera on burns, haemorrhoidectomy patients and skin biopsies. Aloe vera mucilage did not increase burn healing compared with silver sulfadiazine (risk ratio (RR) 1.41, 95% confidence interval (CI) 0.70 to 2.85). A reduction in healing time with Aloe vera was noted after haemorrhoidectomy (RR 16.33 days, 95% CI 3.46 to 77.15) and there was no difference in the proportion of patients completely healed at follow up after skin biopsies. In people with chronic wounds, one trial found no statistically significant difference in pressure ulcer healing with Aloe vera (RR 0.10, 95% CI -1.59 to 1.79) and in a trial of surgical wounds healing by secondary intention Aloe vera significantly delayed healing (mean difference 30 days, 95% CI 7.59 to 52.41). Clinical heterogeneity precluded meta-analysis. The poor quality of the included trials indicates that the trial results must be viewed with extreme caution as they have a high risk of bias. AUTHORS' CONCLUSIONS: There is currently an absence of high quality clinical trial evidence to support the use of Aloe vera topical agents or Aloe vera dressings as treatments for acute and chronic wounds

Honey is a viscous, supersaturated sugar solution derived from nectar gathered and modified by the honeybee, Apis mellifera. Honey has been used since ancient times as a remedy in wound care. Evidence from animal studies and some trials has suggested honey may accelerate wound healing. The objective was to determine whether honey increases the rate of healing in acute wounds (burns, lacerations and other traumatic wounds) and chronic wounds (venous ulcers, arterial ulcers, diabetic ulcers, pressure ulcers, infected surgical wounds). We searched the Cochrane Wounds Group Specialised Register (May 2008), CENTRAL (May 2008) and several other electronic databases (May 2008). Bibliographies were searched and manufacturers of dressing products were contacted for unpublished trials. Randomised and quasi randomised trials that evaluated honey as a treatment for any sort of acute or chronic wound were sought. There was no restriction in terms of source, date of publication or language. Wound healing was the primary endpoint. Data from eligible trials were extracted and summarised using a data extraction sheet by one author and independently verified by a second author. 19 trials (n=2554) were identified that met the inclusion criteria. In acute wounds, three trials evaluated the effect of honey in acute lacerations, abrasions or minor surgical wounds and nine trials evaluated the effect the honey in burns. In chronic wounds two trials evaluated the effect of honey in venous leg ulcers and one trial in pressure ulcers, infected post-operative wounds, and Fournier's gangrene respectively. Two trials recruited people with mixed groups of chronic or acute wounds. The poor quality of most of the trial reports means the results should be interpreted with caution, except in venous leg ulcers. In acute wounds, honey may reduce time to healing compared with some conventional dressings in partial thickness burns (WMD -4.68 days, 95%CI -4.28 to -5.09 days). All the included burns trials have originated from a single centre, which may have impact on replicability. In chronic wounds, honey in addition to compression bandaging does not significantly increase healing in venous leg ulcers (RR 1.15, 95%CI 0.96 to 1.38). There is insufficient evidence to determine the effect of honey compared with other treatments for burns or in other acute or chronic wound types. Honey may improve healing times in mild to moderate superficial and partial thickness burns compared with some conventional dressings. Honey dressings as an adjuvant to compression do not significantly increase leg ulcer healing at 12 weeks. There is insufficient evidence to guide clinical practice in other areas.

Honey is a viscous, supersaturated sugar solution derived from nectar gathered and modified by the honeybee, Apis mellifera. Honey has been used since ancient times as a remedy in wound care. Evidence from animal studies and some trials has suggested that honey may accelerate wound healing. The objective was to determine whether honey increases the rate of healing in acute wounds (e.g. burns, lacerations) and chronic wounds (e.g. skin ulcers, infected surgical wounds). For this first update of the review we searched the Cochrane Wounds Group Specialised Register (searched 13 June 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5); Ovid MEDLINE (2008 to May Week 5 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations 12 June 2012); Ovid EMBASE (2008 to 2012 Week 23); and EBSCO CINAHL (2008 to 8 June 2012). Randomised and quasi-randomised trials that evaluated honey as a treatment for any sort of acute or chronic wound were sought. There was no restriction in terms of source, date of publication or language. Wound healing was the primary endpoint. Data from eligible trials were extracted and summarised by one review author, using a data extraction sheet, and independently verified by a second review author. We identified 25 trials (with a total of 2987 participants) that met the inclusion criteria, including six new trials that were added to this update. In acute wounds, three trials evaluated the effect of honey in acute lacerations, abrasions or minor surgical wounds and 12 trials evaluated the effect of honey in burns. In chronic wounds, two trials evaluated the effect of honey in venous leg ulcers, and single trials investigated its effect in infected post-operative wounds, pressure injuries, cutaneous Lieshmaniasis, diabetic foot ulcers and Fournier's gangrene. Three trials recruited people into mixed groups of chronic or acute wounds. Most trials were at high or unclear risk of bias. In acute wounds, specifically partial-thickness burns, honey might reduce time to healing compared with some conventional dressings (WMD -4.68 days, 95%CI -4.28 to -5.09 days), but, when compared with early excision and grafting, honey delays healing in partial- and full-thickness burns (WMD 13.6 days, 95% CI 10.02 to 17.18 days). In chronic wounds, honey does not significantly increase healing in venous leg ulcers when used as an adjuvant to compression (RR 1.15, 95% CI 0.96 to 1.38), and may delay healing in cutaneous Leishmaniasis when used as an adjuvant to meglumine antimoniate compared to meglumine antimoniate alone (RR 0.72, 95% CI 0.51 to 1.01). Honey dressings do not increase rates of healing significantly in venous leg ulcers when used as an adjuvant to compression. Honey may delay healing in partial- and full-thickness burns in comparison to early excision and grafting, and in cutaneous Leishmaniasis when used as an adjuvant with meglumine antimoniate. Honey might be superior to some conventional dressing materials, but there is considerable uncertainty about the replicability and applicability of this evidence. There is insufficient evidence to guide clinical practice in other types of wounds, and purchasers should refrain from providing honey dressings for routine use until sufficient evidence of effect is available.

Randomised clinical trials (RCTs) to evaluate diabetic foot wound therapies have systematically eliminated large acute wounds from evaluation, focusing only on smaller chronic wounds. The purpose of this study was to evaluate the proportion and rate of wound healing in acute and chronic wounds after partial foot amputation in individuals with diabetes treated with negative pressure wound therapy (NPWT) delivered by the vacuum-assisted closure (VAC) device or with standard wound therapy (SWT). This study constitutes a secondary analysis of patients enrolled in a 16-week RCT of NPWT: 162 open foot amputation wounds (mean wound size = 20.7 cm(2)) were included. Acute wounds were defined as the wounds less than 30 days after amputation, whereas chronic wounds as the wounds greater than 30 days. Inclusion criteria consisted of individuals older than 18 years, presence of a diabetic foot amputation wound up to the transmetatarsal level and adequate perfusion. Wound size and healing were confirmed by independent, blinded wound evaluators. Analyses were done on an intent-to-treat basis. There was a significantly higher proportion of acute wounds (SWT = 59; NPWT = 63) than chronic wounds (SWT = 26; NPWT = 14), evaluated in this clinical trial (P = 0.001). There was no significant difference in the proportion of acute and chronic wounds achieving complete wound closure in either treatment group. Despite this finding, the Kaplan-Meier curves demonstrated statistically significantly faster healing in the NPWT group in both acute (P = 0.030) and chronic wounds (P = 0.033). Among the patients treated with NPWT via the VAC, there was not a significant difference in healing as a function of chronicity. In both the acute and the chronic wound groups, results for patients treated with NPWT were superior to those for the patients treated with SWT. These results appear to indicate that wound duration should not deter the clinician from using this modality to treat complex wounds.

Angiogenesis and vasculogenesis: Inducing the growth of new blood vessels and wound healing by stimulation of bone marrow–derived progenitor cell mobilization and homing

Currently, the treatment of persistent non-healing wounds is among the most difficult clinical issues. We studied 20 samples of normal human skin, 10 specimens from patients with acute trauma, and 9 samples from the patients with chronic wounds that did not heal within 2 months. Using multicolor flow cytometry, we found that the resident T lymphocytes (CD3++ and CD3++) are able to locally produce biologically active substances, normalize human skin homeostasis, thus promoting the wound healing. The data obtained indicate that the blood contains mainly +T lymphocytes (p 0.001), while the +T cells detected in wounds represent a population similar to skin cells. We found no difference in the ratio of resident T cells in chronic and acute wounds, and healthy epithelium. Accordingly, non-healing of wounds and chronic clinical course may be caused by dysfunction of T cells. CD69 regulates T cell secretion of growth factors, IFN, IL-17 and IL-22. The relative number of CD69-expressing T cells from the patients with acute wounds was significantly increased, if compared with cells from normal epidermis and chronic wounds (10.5%2.3, 7.6%1.24, and 3.0%1.05, respectively. p 0.001). The number of cells with the CD3++CD69+ phenotype did not differ significantly between all three groups under comparison. Dysregulation of T cell-mediated healing in chronic wounds is caused by reduced production of IGF-1 by resident CD3++T lymphocytes (1.7%0.9 (p 0.001), and CD3++ (0.44%0.02, p 0.001) compared to CD3++T cells derived from acute wounds (13.6%5.6) and CD3++ (8.9%3.1). The + and + T cells isolated from non-healing chronic wounds did not respond to mitogenic stimuli, unlike the cells obtained from acute wounds and healthy skin. In vitro analysis of cytokine secretion by the CD69-deficient dermal T cells showed a lower spontaneous secretion of IL-22 (4.56%2.3 and 23.9%1.05 and 10.6%1.24, respectively; p 0.001) and IL-2 (0.9%0.08 and 22.6%2.5 and 3.9%1.0, and respectively; p 0.01). When analyzing the number of resident skin T cells secreting IL-17, we obtained the following differences for healthy skin (1.4%0.08), acute wounds (11.3%3.2) and chronic wounds (31.7%11.8), thus showing a significant intergroup difference (p 0.001). T lymphocytes in chronic wounds exhibit some functional disorders and are not able to produce biologically active substances that promote physiological tissue regeneration. The results suggest a role of resident T cells in human skin in wound healing processes and provide new insights into the pathogenesis of chronic wounds.

A Canadian specialty nursing association identified the necessity to examine the role and impact of enterostomal (ET) nursing in Canada. We completed a retrospective analysis of the cost-effectiveness and benefits of ET nurse-driven resources for the treatment of acute and chronic wounds in the community. This was a multicenter retrospective pragmatic chart audit of 3 models of nursing care utilizing 4 community nursing agencies and 1 specialty company owned and operated by ET nurses. An analysis was completed using quantitative methods to evaluate healing outcomes, nursing costs, and cost-effectiveness. Kaplan-Meier estimates were calculated to determine the average time to 100% healing of acute and chronic wounds and total nursing visit costs for treatment in a community setting. Average direct nursing costs related to management of each wound were determined by number of nursing visits and related reimbursement for each visit. A Monte Carlo simulation method was used to help account for costs and benefits in determination of cost-effectiveness between caring groups and the uncertainty from variation between patients and wounds. Three hundred sixty chronic wounds and 54 acute surgical wound charts were audited. Involvement of a registered nurse (RN) with ET or advanced wound ostomy skills (AWOS) in community-level chronic and acute wound care was associated with lower overall costs mainly due to reduced time to 100% closure of the wound and reduced number of nursing visits. The differences in health benefits and total costs of nursing care between the ET/AWOS and a hybrid group that includes interventions developed by an ET nurse and followed by general visiting nurses that could include both RNs and registered practical nurses is an expected reduction in healing times of 45 days and an expected cost difference of $5927.00 per chronic wound treated. When outcomes were broken into ET/AWOS involvement categories for treatment of chronic wounds, there was a significantly faster time to 100% closure at a lower mean cost as the ET/AWOS involvement increased in the case. For acute wound treatment, the differences in health benefits and total costs between the ET/AWOS and a hybrid nursing care model were an expected reduction in healing times of 95 days and an expected cost difference of $9578.00 per acute wound treated. Again, there was a significant difference in healing times and reduced mean cost as the ET/AWOS became more involved in the treatment. The financial benefit to the Ontario Ministry of Health and Long-Term Care is estimated to increase as the involvement of nurses with ET/AWOS specialty training increases. The greater the involvement both directly and indirectly of an ET/AWOS nurse in the management of wounds, the greater the savings and the shorter the healing times.

Topically applied opioids promote angiogenesis and healing of ischemic wounds in rats. We examined if topical fentanyl stimulates wound healing in diabetic rats by stimulating growth-promoting signaling, angiogenesis, lymphangiogenesis and nerve regeneration. We used Zucker diabetic fatty rats that develop obesity and diabetes on a high fat diet due to a mutation in the Leptin receptor. Fentanyl blended with hydrocream was applied topically on ischemic wounds twice daily, and wound closure was analyzed regularly. Wound histology was analyzed by hematoxylin and eosin staining. Angiogenesis, lymphangiogenesis, nerve fibers and phospho-platelet derived growth factor receptor-β (PDGFR-β) were visualized by CD31-, lymphatic vessel endothelium-1, protein gene product 9.5- and anti-phospho PDGFR-β-immunoreactivity, respectively. Nitric oxide synthase (NOS) and PDGFR-β signaling were analyzed using Western immunoblotting. Fentanyl significantly promoted wound closure as compared to phosphate-buffered saline (PBS). Histology scores were significantly higher in fentanyl-treated wounds, indicative of increased granulation tissue formation, reduced edema and inflammation, and increased matrix deposition. Fentanyl treatment resulted in increased wound angiogenesis, lymphatic vasculature, nerve fibers, nitric oxide, NOS and PDGFR-β signaling as compared to PBS. Phospho-PDGFR-β co-localized with CD31 co-staining for vasculature. Topically applied fentanyl promotes closure of ischemic wounds in diabetic rats. Increased angiogenesis, lymphangiogenesis, peripheral nerve regeneration, NO and PDGFR-β signaling are associated with fentanyl-induced tissue remodeling and wound healing.

Differences in Cellular Infiltrate and Extracellular Matrix of Chronic Diabetic and Venous Ulcers Versus Acute Wounds

Dear Sir Malaria with estimated annual global mortality from 700,000 to 2.7 million, caused by Plasmodium falciparum, the most deadly Plasmodium species prevails mainly in Africa (1,2). The pleomorphic clinical outcomes display a remarkable range of disease from acute primary stages to complicated clinical presentations, depending on the transmission intensity, age, immunity and genetic background of the affected individuals (3). Cerebral malaria (CM) is one of the manifestations of sever malaria with enormous morbidity and mortality worldwide. It affects approximately more than 500 million people annually, primarily in sub-Saharan Africa (WHO 2011). CM with the high case fatality rate remains one of the major causes of acquired disability throughout much of the tropical and subtropical world plagued by malaria (4,5). It imposes a substantial economic and palliative care and cost burden to households, which impedes economic development in countries with low national gross products. CM is characterised by a generalised systemic process with high overall level of cytokines related to predominant Th1 response. The shift of immune balance towards Th1 arm is simultaneous with under presentation of the Th2/T (reg) immune regulatory (5). Overproduction of Th1-related proinflammatory cytokines, mainly as interferon-γ, tumour necrosis factor-α (TNF-α), interleukin-1b (IL-1b) and IL-6 combined with underproduction of Th2-related anti-inflammatory cytokines, mainly as IL-10, IL-4 and transforming growth factor-β (TGF-β) is seen in CM (6,7). Raised levels of proinflammatory cytokines have been consistently observed in the cases affected with CM followed by schizont rupture (8). Th1-related proinflammatory cytokines modulate production of eicosanoides (prostaglandines and leukotrienes), thromboxane B2, 5-LOX, phospholipase A2, COX1 and COX2 in peripheral circulation (9). The balance between induced immune suppressive versus immune stimulating state by prostaglandins and leukotrines, respectively, is critical for development of CM (9). Finally, these excreted inflammatory mediators lead to the upregulation of intercellular adhesion molecule-1 (ICAM-1), nitric oxide (NO) production and immune proliferation within spleen (10,11). The pathological scenario evolved from these molecular events is enhanced vessel leakage following pronounced cytoadherence of parasitised erythrocytes and activated mononuclear cells to vascular endothelial cells (6). Preliminary animal and human investigations showed that prior infection with parasites such as Schistosoma hematonium, Ascaris lumbricoides and hookworms has been associated with reduced malaria severity in an age and dose-dependent manner (6,12). Pre-existing helmintic infection has been shown to exert 64% protection against murine CM (6). The suppression of both cellular and humoral immune responses essential for establishment and maintenance of coinfected parasites has been speculated as the main mechanism (13). This competitive parasitic milieu is owned by the influential effects of excessive production of IL-4 and IL-10 by stimulated Th2 lymphocytes and decreased Th1 responses (6). Decreased TNF-α production and IL-6 secretion could simply reflect amplified Th2 responses through non specific B lymphocyte presentation (13). This pattern of cytokine expression is also observed consistently in non CM (6). The induced CD23/NO pathway, increased immunoglobulin E concentrations, decreased ICAM-1 expression and cytoadherence of parasitised red blood cells exert additive effects in this context (12). Therefore, it is translated clinically that factors which alter the polarisation of naÏve T helper cells towards the Th2 phenotype can potentially improve disease profile. Several factors rather than pathogens can influence the host immune network particularly those causing chronic inflammation. Chronic non healing wounds, associated with arose chronic inflammatory state, alter the sum of Th1 versus Th2/T (reg) cytokines with promoted differentiation of precursor Th cells into the Th1 subset (14). Mutually, wounds might get chronic non healing state by standing in deteriorating Th1-dominant immune milieu. Complex inflammatory cascade in chronic non healing wounds is extensively characterised by suppression of IL-10, a prowound healing cytokine (14). Thus coexistence of persistent wounds might play a role in changing the clinical course of CM through elicited pathogenic Th1-type immune response. Lack of IL-10 predominance in chronic non healing wounds is such event seen in episodes of CM (6). The observed microcirculatory dysfunction and angiogenic failure in chronic non healing wounds is a favoured milieu for induction of CM's pathogenesis (15,16). Hence, non healing wounds would synergistically enhance load on immune system in CM. The possible influence of chronic wounds on the acquisition of immunity against CM would likely result in a higher rate of CM. This combination might confer lethality and exacerbation of symptoms. It needs to be determined at the population level whether patients with underlying chronic non healing wounds require a higher sequestered parasite biomass to develop CM or not. Each stage of wound carriage might play an important role in shaping the immunity against malaria and CM and this shared exposure should not be neglected simply. Both of these multifactorial diseases are largely seen in association with poor nutrition and socioeconomic status. The possible influence of chronic wounds on the immune response to malaria, parasite development and cytoadherence phenomena needs to be determined. Chronic non healing wounds continue to be a pandemic health problem (17). Animal studies would be of paramount value in this regard. Chronic wounds are major public-health problem in developing countries prone to CM: coendemic. The possibility that chronic non healing wounds could markedly affect the CM disease burden in malaria endemic area and their relevance to clinical disease deserves further investigations. Comparison between rate of CM resistance or tolerance between population widely devastated by chronic wounds and wound-free areas will illuminate the possible wound–CM interaction. Comparison of wound distribution among sites with peak occurrence of CM and variable malaria transmission intensities also seems helpful. This implies that treating one burden (wounds) could potentially relieve the other (CM), but it is not yet clinically proved. This would offer affordable means to roll back CM and its consequent complications and costs. If deleterious effects of concomitant non healing wounds on CM are confirmed, vigorous therapeutic measures for chronic wounds might become a priority in malaria endemic area before the progress towards CM. Perhaps, little paid attentions to the pre-existing non healing wounds merely before the onset of rainy seasons with the peak malaria transmissions would be of paramount impact on CM elimination. This seasonal attention to wounds or even every factor able to aggravate much of the hyperimmune responsiveness associated with CM expected to be economically more cost effective. The data regarding favoured season could be derived from district statistics and informed to resident clinicians. Considering the high prevalence of chronic non healing wounds in malaria endemic area as sub-Saharan Africa and the fatality rate of CM in this area, the fundamental practical implication of dewounding on the outcome of CM will be perceived easier. It is also convincible to address this hypothesis that wounds will get non healing fate in the cases experienced fatal CM. Mohaddeseh Behjati 1 The author declares no conflicts of interest.

Chronic wounds are a challenge to treatment. In this retrospective study, the effect of transdermal CO2 application on wound healing in chronic ulcers was investigated and compared to the effect of CO2 on acute surgical wounds. Eighty-six patients (52 females and 34 males) with chronic wounds of different origin except arterial occlusive disease were included. In addition, 17 patients (5 females, 12 males) with wide excision wounds after surgical therapy of acne inversa were considered. The indication for CO2 application was a wound at risk for infection. Treatment was performed with a Carboflow device once daily for 30 to 60 minutes. There was clinical evidence of improvement of granulation and reduction of discharge and malodor within 1 week of treatment in both chronic and acute wounds. Only 9 patients, all diabetics, needed an additional systemic antibiosis. The treatment was well tolerated. No adverse effects have been noted. Transdermal CO2 application is a useful method to reduce the risk of infection and improve wound healing in both chronic and certain acute wounds. Systematic prospective trials are needed.