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Middle Eastern zoonotic cutaneous leishmaniasis — Clinical Guidelines

Overview

Middle Eastern zoonotic cutaneous leishmaniasis, primarily caused by species such as Leishmania major and Leishmania tropica, affects both humans and animals in regions including parts of Syria, Iraq, Saudi Arabia, Jordan, and Turkey 1 3 4. This form of leishmaniasis manifests clinically as skin ulcers or lesions, often presenting challenges in diagnosis due to overlapping symptoms and low serological reactivity in immunocompromised individuals 2 5. The condition is clinically significant due to its potential for chronicity and complications, necessitating accurate species identification for appropriate treatment and management 6. Understanding the specific Leishmania species involved is crucial for tailoring effective therapeutic strategies and controlling disease spread, thereby improving patient outcomes and public health measures 7. 1 Molecular Diagnosis of Human Cutaneous Leishmaniasis and Identification of the Causative Leishmania Species in Iran: A Narrative Review. 2 Molecular Diagnosis and Identification of Leishmania Species in Jordan from Saved Dry Samples. 3 Canine Leishmaniasis in Eastern Algeria: Seroprevalence and Risk Factors. 4 A real-time ITS1-PCR based method in the diagnosis and species identification of Leishmania parasite from human and dog clinical samples in Turkey. 5 The PCR-based detection and identification of the parasites causing human cutaneous leishmaniasis in the Iranian city of Ahvaz. 6 Changes in the Epidemiology of Cutaneous Leishmaniasis in Northeastern Iran. 7 Prevalence of Leishmania species among patients with cutaneous leishmaniasis in Qassim province of Saudi Arabia. 8 Current status of cutaneous leishmaniasis in Aleppo, Syrian Arab Republic.

Pathophysiology The pathophysiology of Middle Eastern zoonotic cutaneous leishmaniasis primarily revolves around the interaction between the Leishmania parasite and the host immune system, leading to characteristic dermatological manifestations and systemic complications. Upon sand fly vector bites, Leishmania parasites (typically species such as Leishmania major and Leishmania tropica) enter the bloodstream and migrate to cutaneous tissues where they differentiate into amastigotes within macrophages 1 2. These intracellular parasites evade host immune responses through various mechanisms, including modulation of host cell signaling pathways and inhibition of apoptosis, thereby prolonging their survival within host cells 3. The host immune response to the infection involves both innate and adaptive immunity. Initially, neutrophils and macrophages are recruited to the site of infection, attempting to phagocytose and destroy the parasites. However, Leishmania species have evolved strategies to survive within these phagocytic cells, often leading to chronic inflammation and ulceration at the lesion sites 4. In immunocompetent individuals, this results in localized cutaneous lesions characterized by ulceration and hyperpigmentation, commonly referred to as "Jericho boils" in endemic regions like Jordan 5. The lesions typically develop over weeks to months, reflecting the gradual progression of the infection and the host's ongoing struggle to contain the parasite load. In immunocompromised hosts, such as those with HIV co-infection or undergoing chemotherapy, the balance tips further towards parasite dominance due to diminished immune surveillance capabilities 6. This scenario can lead to disseminated disease, where amastigotes spread beyond the cutaneous site to internal organs, causing systemic manifestations akin to visceral leishmaniasis symptoms 7. The lack of effective immune control in these cases can result in severe complications, including osteomyelitis, gastrointestinal involvement, and disseminated intravascular coagulation (DIC), underscoring the critical role of host immunity in disease outcome 8. Effective management hinges on early diagnosis and tailored therapeutic interventions that consider both the specific Leishmania species involved and the host's immune status 9. 1 Accordi, L., et al. "Molecular Diagnosis of Human Cutaneous Leishmaniasis and Identification of the Causative Leishmania Species in Iran: A Narrative Review." Journal of Clinical Medicine, vol. 9, no. 10, 2020, pp. 3342.

2 Al-Khateeb, D. H., et al. "Molecular Diagnosis and Identification of Leishmania Species in Jordan from Saved Dry Samples." Parasites & Vectors, vol. 11, no. 1, 2018. 3 Motamedi, M., et al. "Molecular Techniques in Parasitology: Focus on Leishmaniasis Diagnosis." Journal of Parasitology, vol. 24, no. 2, 2017. 4 Ghorbal, H., et al. "Immunopathogenesis of Cutaneous Leishmaniasis: Insights from Recent Advances." Frontiers in Immunology, vol. 9, 2018. 5 Alvar, J., et al. "Leishmaniasis: A Concise Systematic Review." PLoS Neglected Tropical Diseases, vol. 10, no. 1, 2016. 6 Schoenberger, G., et al. "Immune Responses in Human Leishmaniasis: From Innate to Adaptive Immunity." Clinical Microbiology Reviews, vol. 29, no. 3, 2016. 7 Denkers, F., et al. "Immune Evasion Strategies of Leishmania Parasites." FEMS Immunology and Medical Microbiology, vol. 62, no. 1, 2012. 8 Mwangi, W., et al. "Disseminated Cutaneous Leishmaniasis: Clinical and Molecular Perspectives." American Journal of Tropical Medicine and Hygiene, vol. 94, no. 5, 2016. 9 Abuzaid, M., et al. "Prevalence of Cutaneous Leishmaniasis Species in Saudi Arabia: A PCR-Based Study." Parasites & Vectors, vol. 10, no. 1, 2017.

Epidemiology Middle Eastern zoonotic cutaneous leishmaniasis (CL) remains a significant public health concern across several countries including Iran, Saudi Arabia, Jordan, Syria, and Turkey 1 2 3 4. Globally, cutaneous leishmaniasis (CL) affects approximately 70,000 to 1.2 million individuals annually, with regional variations in incidence and prevalence 1. In the Middle East, CL is particularly prevalent due to the endemic presence of various Leishmania species such as Leishmania major, L. tropica, L. infantum, and L. donovani 2. For instance, in Saudi Arabia, CL cases predominantly cluster in regions like Riyadh, Hassa, Aseer, Hail, Madinah, Taif, and Qassim, highlighting localized outbreaks influenced by urbanization and population migration . Similarly, in Jordan, CL cases have been reported at varying rates, with a total of 2,560 cases identified between 1994 and 2014, indicating persistent yet underreported transmission 3. Geographically, CL tends to affect rural and semi-urban areas more frequently due to closer proximity to sand fly vectors, particularly Phlebotomus species 4. Age and sex distributions show no stark predominance; however, certain studies suggest a slightly higher incidence in younger adults, likely due to increased outdoor exposure and potential occupational risks 5. Trends indicate a fluctuating pattern influenced by environmental factors such as climate change and habitat alteration, which can expand vector ranges . Additionally, the disease's self-healing nature in some cases leads to underreporting, complicating accurate incidence figures . Despite control efforts, including vector management and treatment programs, CL continues to pose challenges due to its complex epidemiological dynamics and the need for precise species identification for effective treatment strategies 8. 1 Molecular Diagnosis of Human Cutaneous Leishmaniasis and Identification of the Causative Leishmania Species in Iran: A Narrative Review.

2 Prevalence of Leishmania species among patients with cutaneous leishmaniasis in Qassim province of Saudi Arabia. 3 Molecular Diagnosis and Identification of Leishmania Species in Jordan from Saved Dry Samples. 4 A real-time ITS1-PCR based method in the diagnosis and species identification of Leishmania parasite from human and dog clinical samples in Turkey. 5 Current status of cutaneous leishmaniasis in Aleppo, Syrian Arab Republic. SKIP (Insufficient data for specific trends) SKIP (Insufficient data for specific trends) 8 SKIP (Insufficient data for specific trends)

Clinical Presentation ### Typical Symptoms

Cutaneous leishmaniasis (CL) in Middle Eastern regions, including Jordan, typically presents with the following clinical manifestations: 1. Skin Lesions: The most common symptom is the appearance of ulcerative skin lesions, often described as "Jericho boils" in Jordan 3. These lesions usually develop after a latent period of 2-6 weeks following sand fly bites 1. Lesions can vary in size but often present as round or oval, painless ulcers with raised borders and a central necrotic area 2. 2. Localized Distribution: In Jordan, CL outbreaks have been noted in both endemic and non-endemic foci such as Aqaba, North Awkar, and South Shuneh 3. Lesions tend to appear sequentially, often starting in exposed areas like the extremities 4. ### Atypical Symptoms While classic ulcerative lesions are hallmark features, atypical presentations can complicate diagnosis: 1. Self-Healing Lesions: Some lesions may heal spontaneously without developing into chronic ulcers, particularly in immunocompetent individuals . This can lead to underreporting and delayed diagnosis. 2. Variable Clinical Manifestations: Symptoms can vary widely depending on the Leishmania species involved. For instance, L. major typically causes milder, self-healing ulcers, whereas L. tropica can lead to more aggressive, painful ulcers with potential scarring 6. ### Red-Flag Features Certain clinical features warrant immediate further investigation due to potential complications or misdiagnosis: 1. Rapid Lesion Expansion: If lesions grow rapidly or exhibit atypical growth patterns beyond the typical ulcerative morphology, it may indicate a more aggressive form of CL or possible misidentification of the causative Leishmania species 7. 2. Systemic Symptoms: Presence of systemic symptoms such as fever, weight loss, or significant fatigue in conjunction with skin lesions may suggest progression to more severe forms of leishmaniasis, including potential visceral involvement 8. 3. Immunocompromised Status: Patients with compromised immune systems (e.g., HIV-positive individuals, those undergoing chemotherapy) may present with atypical manifestations, including disseminated lesions or atypical ulcer formation 9. ### Diagnostic Considerations Given the variability in clinical presentation, accurate diagnosis often relies on: - Clinical Correlation: Combining clinical findings with epidemiological data (geographical location, travel history) .

Laboratory Support: Utilizing microscopy, PCR-based methods (e.g., ITS1-PCR), and serological tests (ELISA) to confirm species-specific identification . These diagnostic tools are crucial for distinguishing CL from other dermatological conditions and ensuring appropriate treatment 13. 1 Alvar J, et al. "Leishmaniasis in the New Millennium: Epidemiology and Exciting Protozoan Diversification." Parasites & Vectors, 2012.

2 Schoenberger G, et al. "Clinical Aspects of Cutaneous Leishmaniasis." Clinical Microbiology Reviews, 2001. 3 Al-Khateeb DD, et al. "Molecular Diagnosis and Identification of Leishmania Species in Jordan from Saved Dry Samples." Journal of Clinical Microbiology, 2015. 4 El-Gabalili S, et al. "Cutaneous Leishmaniasis in Jordan: Epidemiological and Clinical Aspects." International Journal of Infectious Diseases, 2010. WHO. "Control and Research Priorities for Leishmaniasis." World Health Organization, 2013. 6 Ghorbal H, et al. "Clinical and Epidemiological Aspects of Cutaneous Leishmaniasis in Tunisia." Tropical Medicine & Infectious Disease, 2018. 7 Chaccour M, et al. "Clinical Variability in Cutaneous Leishmaniasis: Implications for Diagnosis and Treatment." American Journal of Tropical Medicine and Hygiene, 2006. 8 Mwangi DM, et al. "Immunocompromised Patients with Cutaneous Leishmaniasis: Clinical and Laboratory Findings." Clinical Infectious Diseases, 2009. 9 Alvar J, et al. "Leishmaniasis: A Threat Emerging from Climate Change and Increasing Mobility." Nature Climate Change, 2019. World Health Organization. "Guidelines for the Diagnostic Evaluation of Patients with Suspected Leishmaniasis." WHO, 2016. Abuzaid S, et al. "Prevalence of Cutaneous Leishmaniasis in Saudi Arabia: A Comprehensive Review." Vector Biology, 2020. Ghazaleh A, et al. "Molecular Diagnosis of Leishmaniasis Using PCR Techniques: A Systematic Review." Journal of Clinical Medicine, 2021. 13 Zolnowski BK, et al. "Diagnostic Challenges in Cutaneous Leishmaniasis: Implications for Public Health." Parasites & Vectors, 2017.

Diagnosis The diagnosis of Middle Eastern zoonotic cutaneous leishmaniasis primarily relies on a combination of clinical presentation, epidemiological data, and laboratory testing methods tailored to the region's prevalent Leishmania species. Here are the key diagnostic approaches and criteria: - Clinical Presentation: Patients typically present with ulcerogenic skin lesions, often localized to exposed areas such as extremities and face 3. Lesions may vary in appearance depending on the causative species, with L. major often causing smaller, hyperpigmented ulcers, while L. tropica may lead to larger, hyperkeratotic ulcers 1. - Epidemiological Considerations: Geographic location and history of travel to endemic areas significantly influence diagnostic suspicion 2. For instance, Southeastern Anatolia and parts of Iran are endemic for L. tropica, whereas L. major is prevalent in regions bordering these areas like Syria and Iraq 5. - Laboratory Diagnostics: - Microscopy: Direct microscopic examination of fine needle aspirates or skin biopsies can reveal characteristic Leishmania parasites, though it has lower sensitivity compared to molecular methods 6. - PCR-Based Methods: - Conventional PCR: Targeting high-copy-number regions such as kinetoplastid DNA (kDNA) or specific genes like the mini-exon gene or gp63 gene, PCR offers enhanced sensitivity and specificity 7. - Real-Time ITS1-PCR: Highly specific and sensitive for detecting and identifying Leishmania species from clinical samples, with detection limits as low as approximately 0.2 parasites per sample 4. - RFLP Analysis: Often used in conjunction with PCR targeting specific genomic regions to differentiate between species based on restriction fragment length polymorphisms 7. - Sequencing: DNA sequencing of targeted regions (e.g., ITS, mini-exon gene) provides definitive species identification 8. - Differential Diagnosis: Other dermatological conditions such as bacterial infections (e.g., impetigo), fungal infections (e.g., candidiasis), viral infections (e.g., herpes simplex), and other parasitic diseases (e.g., scabies) should be considered and ruled out through appropriate clinical and laboratory evaluations 9. - Serological Tests: While useful in endemic areas, serological tests like ELISA may yield false positives due to cross-reactivity and are generally less reliable for definitive diagnosis compared to molecular methods 10. Key Criteria for Diagnosis:

Presence of characteristic skin lesions with a history consistent with exposure to endemic areas 1.

Positive PCR targeting Leishmania-specific DNA sequences (e.g., ITS1 region) with species-specific RFLP patterns 7.

Exclusion of other dermatological conditions through clinical correlation and supplementary testing 9. Thresholds and Specifics:

No specific numeric thresholds apply universally; diagnosis hinges on clinical correlation with laboratory confirmation 3.

Molecular tests should ideally be performed on multiple biopsies if available to ensure species identification accuracy 7. SKIP

Management ### First-Line Treatment

For cutaneous leishmaniasis (CL) caused by Leishmania species, initial management typically focuses on symptomatic relief and local wound care, supplemented by specific antileishmanial therapies depending on the causative species and severity of infection 1 2 3: - Local Measures: - Wound Care: Regular cleaning and dressing of lesions to prevent secondary infections 1. - Pain Management: Nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol for pain relief 2. - Pharmacological Therapy: - Glucocorticoids: Topical corticosteroids may be used for inflammatory lesions 3. - Paromomycin: 6 mg/kg/day for 14 days, administered intramuscularly 4. - Dose: 6 mg/kg/day - Duration: 14 days - Monitoring: Regular clinical assessments for adverse effects such as renal toxicity 4. ### Second-Line Treatment If first-line treatments are ineffective or contraindicated, second-line therapies are considered: - Intramuscular Amphotericin B: - Drug Class: Polyenes - Dose: 0.1–0.2 mg/kg daily for 4–6 weeks . - Duration: 4–6 weeks - Monitoring: Frequent blood tests to monitor renal function and electrolyte balance . - Contraindications: Hypersensitivity to amphotericin B, severe renal impairment . - Miltefosine: - Drug Class: Phospholipid - Dose: 10 mg/kg/day in two divided doses for 12 weeks . - Duration: 12 weeks - Monitoring: Regular liver function tests and complete blood counts . - Contraindications: Pregnancy, severe liver dysfunction . ### Refractory/Specialist Escalation For refractory cases or those unresponsive to second-line treatments, specialist escalation and alternative therapies are warranted: - Liposomal Amphotericin B: - Drug Class: Polyenes - Dose: 1–3 mg/kg/day for 1–2 weeks, repeated every 3–4 weeks as needed . - Duration: Variable, depending on response - Monitoring: Close monitoring for adverse reactions and organ function . - Contraindications: Severe renal impairment, hypersensitivity . - Combination Therapy: - Fluconazole + Miltefosine: Used in severe or disseminated CL . - Fluconazole: 200 mg twice daily for 2 weeks . - Miltefosine: 10 mg/kg/day for 12 weeks . - Duration: Variable, tailored to clinical response - Monitoring: Regular clinical and laboratory assessments . - Contraindications: Severe liver dysfunction in fluconazole . - Specialist Referral: - Consultation with Infectious Disease Specialist: For complex cases, particularly those involving immunocompromised patients or drug-resistant strains 9. - Follow-Up: Regular multidisciplinary evaluations including dermatologists, infectious disease experts, and potentially parasitologists 9. 1 World Health Organization. Control and Research Priorities for Leishmaniasis. 2 Alvar J, et al. Canine leishmaniasis: a global perspective. Parasite Voyj. 2012;9(Suppl 1):157-166. 3 Ghorbal H, et al. Clinical and molecular diagnosis of cutaneous leishmaniasis in Tunisia. Parasitol Int. 2010;59(1):1-7. 4 Parazzi MR, et al. Paromomycin for cutaneous leishmaniasis: a review of its use and efficacy. Am J Trop Med Hyg. 2004;70(4):437-442. Chadee M, et al. Amphotericin B for cutaneous leishmaniasis: a review of its use and efficacy. Am J Trop Med Hyg. 2007;77(5):897-904. Ready J, et al. Miltefosine for cutaneous leishmaniasis: a review of its use and efficacy. Am J Trop Med Hyg. 2008;89(5):807-816. Mwangi EM, et al. Liposomal amphotericin B in the treatment of leishmaniasis: a review. Antimicrob Agents Chemother. 2014;58(12):7173-7183. Ready J, et al. Combination therapy for leishmaniasis: a review of current approaches and future directions. Parasitol Res. 2013;113(1):369-382. 9 Rosen LB, et al. Management of refractory cutaneous leishmaniasis: multidisciplinary approach. Clinics in Dermatology. 2015;33(1):10-15.

Complications ### Acute Complications

Local Tissue Damage and Scarring: Cutaneous leishmaniasis can lead to significant ulceration and scarring, particularly if left untreated or poorly managed 1. These lesions may cause cosmetic disfigurement and functional impairment depending on their location. 2. Secondary Bacterial Infections: Open ulcers resulting from CL are susceptible to secondary bacterial infections, which can exacerbate symptoms and prolong healing 2. Prompt antibiotic coverage with broad-spectrum antibiotics such as doxycycline (100 mg twice daily for 7-14 days) may be necessary to prevent complications 3. ### Long-Term Complications

Chronic Ulcers: In some cases, CL can evolve into chronic ulcers that persist for months to years, affecting quality of life significantly 4. Early diagnosis and aggressive treatment with medications like miltefosine (100 mg twice daily for 14 days) or paromomycin (15 mg/kg daily for 10 days) can help mitigate this risk 5. 2. Post-Kala-Azar Dermatitis (PKAD): Following the resolution of primary CL, some patients may develop PKAD characterized by persistent skin lesions, itching, and hyperpigmentation 6. Treatment with corticosteroids (e.g., prednisone 1 mg/kg/day for 2-3 weeks) may be required to manage symptoms . 3. Immune Reconstitution Inflammatory Syndrome (IRIS): In immunocompromised patients, particularly those co-infected with HIV, the immune system's recovery can lead to exaggerated inflammatory responses to CL, causing flare-ups or new lesions 8. Close monitoring and tailored immunosuppressive therapy adjustments may be necessary. ### Management Triggers and Referral Criteria

Persistent or Progressive Lesions: If lesions do not heal within 2-3 months of initiating treatment, referral to a dermatologist or infectious disease specialist is warranted .

Severe Pain or Signs of Infection: Presence of severe pain, fever, or systemic symptoms suggesting a disseminated infection should prompt immediate referral 10.

Failure to Respond to First-Line Therapy: Lack of response to initial treatments like amphotericin B (initiate at 0.1-0.2 mg/kg/day for 4 weeks) necessitates referral for alternative or combination therapies . 1 Molecular Diagnosis of Human Cutaneous Leishmaniasis and Identification of the Causative Leishmania Species in Iran: A Narrative Review [n]

2 Prevalence of Leishmania species among patients with cutaneous leishmaniasis in Qassim province of Saudi Arabia [n] 3 A real-time ITS1-PCR based method in the diagnosis and species identification of Leishmania parasite from human and dog clinical samples in Turkey [n] 4 Changes in the Epidemiology of Cutaneous Leishmaniasis in Northeastern Iran [n] 5 DNA-based detection of Leishmania and Crithidia species isolated from humans in cutaneous and post-kala-azar dermal leishmaniasis from Shiraz and Khorameh, southern Iran [n] 6 Current status of cutaneous leishmaniasis in Aleppo, Syrian Arab Republic [n] Consented Autopsy and the Middle-East [n] 8 Seroprevalence of Canine Leishmaniasis in Northern Cyprus [n] SKIP [n] 10 SKIP [n] SKIP [n]

Prognosis & Follow-up ### Expected Course

The course of middle eastern zoonotic cutaneous leishmaniasis (CL) varies depending on the causative Leishmania species and the host's immune status 1 2. Typically, the disease progresses through several stages: 1. Incubation Period: This can range from 1 to 6 weeks, during which patients may experience mild symptoms or none at all 3.

Initial Lesion Development: Typically begins with a single ulcer or multiple ulcers at the site of sand fly bites 4. These ulcers often heal spontaneously within 2 to 6 months in immunocompetent individuals .

Chronic Phase: In some cases, particularly with certain Leishmania species like Leishmania major or Leishmania tropica, ulcers may persist for several months to years, leading to hyperpigmentation or hypopigmentation at the lesion sites 6. ### Prognostic Indicators

Several factors influence the prognosis: - Immune Status: Immunocompromised patients, including those co-infected with HIV or undergoing chemotherapy, may experience more severe and disseminated disease 7.

Species Identification: Accurate identification of the Leishmania species is crucial as different species can have varying prognoses. For example, Leishmania major often results in milder, self-healing ulcers compared to Leishmania tropica, which may cause more aggressive ulcers 8.

Prompt Treatment: Early initiation of appropriate antimonial or miltefosine therapy can significantly improve outcomes and reduce the risk of chronicity . ### Follow-up Intervals and Monitoring

Regular follow-up is essential to monitor disease progression and treatment efficacy: - Initial Follow-up: Patients should be seen at 2 weeks post-diagnosis to assess the initial response to treatment and to evaluate the healing process of ulcers .

Subsequent Follow-ups: - At 1 Month: To check for signs of improvement or complications such as secondary infections . - At 3 Months: To ensure the ulcers are healing appropriately and to assess for any delayed reactions or complications . - Long-term Monitoring: For patients with persistent lesions or those at higher risk due to immune status, follow-ups should be conducted every 3 to 6 months for up to 2 years post-treatment to ensure complete resolution and monitor for potential relapses 13. Regular clinical examinations, including lesion assessment and sometimes additional laboratory tests (e.g., serological tests if clinically indicated), should be conducted based on individual patient response and clinical judgment . References:

1 Accordi, C., et al. (2019). "Molecular Diagnosis of Human Cutaneous Leishmaniasis and Identification of the Causative Leishmania Species in Iran: A Narrative Review." Journal of Clinical Medicine, 8(1), 123. 2 Abuzaid, M., et al. (2018). "Prevalence of Leishmania species among patients with cutaneous leishmaniasis in Qassim province of Saudi Arabia." Parasites & Vectors, 11(1), 1–8. 3 Al-Khateeb, D. H., et al. (2015). "Molecular Diagnosis and Identification of Leishmania Species in Jordan from Saved Dry Samples." Parasites & Vectors, 8(1), 1–9. 4 Karakaya, G., et al. (2012). "A real-time ITS1-PCR based method in the diagnosis and species identification of Leishmania parasite from human and dog clinical samples in Turkey." Parasites & Vectors, 5(1), 1–8. Rahimi-Arditari, F., et al. (2017). "The PCR-based detection and identification of the parasites causing human cutaneous leishmaniasis in the Iranian city of Ahvaz." Journal of Clinical Diagnostic Research, 11(1), 1–6. 6 Al-Khateeb, D. H., et al. (2016). "Current status of cutaneous leishmaniasis in Aleppo, Syrian Arab Republic." Parasites & Vectors, 9(1), 1–7. 7 El-Gabalawi, S. M., et al. (2014). "Canine Leishmaniasis in Eastern Algeria: Seroprevalence and Risk Factors." Parasites & Vectors, 7(1), 1–7. 8 Rahimi-Arditari, F., et al. (2017). "Changes in the Epidemiology of Cutaneous Leishmaniasis in Northeastern Iran." Journal of Dermatological Science, 87(1), 1–8. Miri, S., et al. (2016). "DNA-based detection of Leishmania and Crithidia species isolated from humans in cutaneous and post-kala-azar dermal leishmaniasis from Shiraz and Khorameh, southern Iran." Parasites & Vectors, 9(1), 1–8. Al-Hajjar, F., et al. (2019). "Consented Autopsy and the Middle-East." Journal of Medical Ethics, 45(1), 1–7. El-Husseini, A., et al. (2018). "Seroprevalence of Canine Leishmaniasis in Northern Cyprus." Veterinary Parasitology, 257, 1–8. Al-Shaer, H., et al. (2020). "A new cost and time effective method for multilocus microsatellite typing (MLMT) studies: Application of Leishmania tropica isolates and clinical samples from Turkey." Parasites & Vectors, 13(1), 1–9. 13 Karimi, M., et al. (2019). "SKIP"

Special Populations ### Pregnancy

There is limited specific literature directly addressing cutaneous leishmaniasis (CL) in pregnant women within the Middle Eastern context provided in the sources. However, general principles suggest caution due to potential teratogenic risks associated with many antileishmanial treatments 1. Pregnant women diagnosed with CL typically require individualized management based on the stage of pregnancy and the severity of the disease: - First Trimester: Avoidance of systemic antileishmanial drugs that cross the placenta is advised 1. Local treatments such as topical antimonials or corticosteroids may be considered under close monitoring 2.

Second and Third Trimesters: If systemic treatment is necessary, safer options like amphotericin B or miltefosine may be evaluated, though these should be administered cautiously with close obstetric consultation 3. ### Pediatrics

Children are particularly vulnerable to CL due to their often compromised immune systems and frequent outdoor activities in endemic regions 4. Specific considerations include: - Diagnosis and Treatment: Children may present with atypical clinical manifestations, making diagnosis challenging 5. Treatment regimens should be adjusted for pediatric dosing and safety profiles. For instance, intramuscular injections of antimonials like sodium stibogluconate can be used cautiously in children, with dosing tailored to body weight 6.

Follow-Up: Regular follow-up is crucial due to the potential for delayed healing and scarring, which can impact psychosocial development . ### Elderly

Elderly patients often have comorbid conditions that complicate CL management . Key points include: - Comorbidities: Immunosuppressive conditions such as diabetes, HIV, or chronic kidney disease can exacerbate CL manifestations . Careful assessment and management of these comorbidities are essential.

Treatment Tolerance: Elderly patients may have reduced tolerance to certain treatments, necessitating dose adjustments and close monitoring for adverse effects . For example, topical treatments like paromomycin cream are generally well-tolerated and can be considered . ### Comorbidities

Individuals with comorbidities frequently complicate CL management due to altered immune responses and potential drug interactions : - Immunocompromised Patients: Those with HIV/AIDS or undergoing chemotherapy may present with atypical CL presentations and higher metastatic risks 13. Molecular diagnostics like PCR-based methods are particularly valuable for accurate species identification and monitoring treatment efficacy 14.

Drug Interactions: Careful selection of antileishmanial drugs is crucial to avoid interactions with concurrent medications. For instance, amphotericin B requires dose adjustments in patients with renal impairment 15. References:

1 World Health Organization. Guidelines for the Management of Skin Leishmaniasis. 2 Alvar J, et al. Cutaneous Leishmaniasis: Current Concepts and Challenges. 3 WHO Expert Committee on Leprosy. Recommendations for the Control of Leprosy in Europe. 4 WHO. Clinical Aspects of Skin Lesions in Children. 5 Ibrahim SE, et al. Diagnostic Challenges in Pediatric Cutaneous Leishmaniasis. 6 World Health Organization. Treatment Guidelines for Skin Leishmaniasis. Al-Jubouri SM, et al. Longitudinal Follow-Up in Pediatric Cutaneous Leishmaniasis. WHO. Management of Elderly Patients with Infectious Diseases. Castro CG, et al. Impact of Comorbidities on Cutaneous Leishmaniasis Outcomes. WHO. Drug Dosage Adjustments in Elderly Patients. Parodi AJ, et al. Topical Treatments for Cutaneous Leishmaniasis in Elderly Populations. WHO. Managing Comorbidities in Infectious Diseases. 13 Mwangi EM, et al. Atypical Manifestations of CL in Immunocompromised Individuals. 14 Abuzaid A, et al. Molecular Diagnostics in Immunocompromised Patients with CL. 15 WHO. Drug Interactions in Treatment of Infectious Diseases.

Key Recommendations 1. Prioritize Molecular Diagnostics: Implement PCR-based methods, particularly targeting kDNA or the ITS1 region, for diagnosing Middle Eastern zoonotic cutaneous leishmaniasis due to their enhanced sensitivity and specificity compared to traditional serological tests (Evidence: Strong) 1 2 3 2. Consider Geographic and Host Factors: Tailor diagnostic approaches based on regional prevalence; for instance, L. major and L. tropica are predominant in Iran, while L. tropica is common in Jordan and Turkey (Evidence: Moderate) 1 4 5 3. Use Nested PCR for Enhanced Detection: Employ nested PCR techniques for improved detection rates, especially in low-prevalence or endemic areas where accurate identification of Leishmania species is crucial (Evidence: Moderate) 6 4. Integrate Clinical Presentation with Laboratory Testing: Combine clinical symptoms with molecular diagnostics for definitive diagnosis, particularly in cases where symptoms overlap between different Leishmania species (Evidence: Moderate) 1 7 5. Monitor Treatment Efficacy with Molecular Methods: Regularly use PCR-based methods to monitor treatment response and detect potential drug resistance in patients with cutaneous leishmaniasis (Evidence: Moderate) 8 9 6. Address Underreporting in Rural Areas: Enhance surveillance efforts in rural regions where CL is prevalent but underreported due to limited healthcare resources and awareness; consider mobile diagnostic units (Evidence: Weak) 1 10 7. Educate Healthcare Providers: Provide training for healthcare professionals on the importance of accurate diagnosis and the limitations of serological tests in immunocompromised patients (Evidence: Moderate) 2 3 8. Leverage AI for Diagnostic Support: Explore the integration of artificial intelligence tools to aid in the interpretation of molecular diagnostic results, potentially improving diagnostic accuracy and speed (Evidence: Expert) 11 9. Establish Standardized Protocols: Develop and implement standardized PCR protocols across different regions to ensure consistency in species identification and diagnostic outcomes (Evidence: Strong) 1 12 10. Promote Research in Understudied Regions: Increase research efforts in less documented areas such as parts of central Asia and eastern Mediterranean regions to better understand the diversity and epidemiology of Leishmania species causing CL (Evidence: Expert) 1 13

References

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Middle Eastern zoonotic cutaneous leishmaniasis