1. Kala-Azar Hasanein Ghali, MD Department of Pediatrics College of Medicine – University of Baghdad December, 28 th, 2015

2. Introduction  Intracellular protozoan parasites of the genus Leishmania, which are transmitted by phlebotomine sandflies.  Multiple species of Leishmania are known to cause human disease involving the skin and mucosal surfaces and the visceral reticuloendothelial organs.  Cutaneous disease is generally mild but may cause cosmetic disfigurement.Visceral leishmaniasis is associated with significant morbidity and mortality.  Dimorphic, existing as : a flagellate promastigote in the insect vector. Aflagellate amastigote, resides and replicates only within the vertebrate host.

3. phlebotomine sandflies

4. Life cycle Infective meatcyclic form Non infective procyclic form Resistant to the acidic, hostile environment of the macrophage and eventually ruptures the cell and goes on to infect other macrophages. Infected macrophages have a diminished capacity to initiate and respond to an inflammatory response, thus providing a safe haven for the parasite.

5. Epidemiology / Pathogenesis The leishmaniases may occur sporadically throughout an endemic region or may occur in epidemic focuses. With only rare exceptions, the Leishmania organisms that primarily cause cutaneous disease do not cause visceral disease. Cutaneous leishmaniasis is caused by L. major and L. tropica. Visceral leishmaniasis is caused by L. donovani and L. infantum. In VL there is prominent reticuloendothelial cell hyperplasia in the liver, spleen, bone marrow, and lymph nodes. Individuals with prior active disease or subclinical infection are usually immune to a subsequent clinical infection.

6. Epidemiology / Pathogenesis Within endemic areas, people who have had a subclinical infection can be identified by a positive delayed-type hypersensitivity response to leishmanial antigens. Subclinical infection occurs considerably more frequently than does active cutaneous or visceral disease. Host factors (concomitant disease, nutritional status), parasite factors (virulence, size of the inoculum), and possibly vector specific factors (vector genotype) influence the expression as either subclinical infection or active disease. Within endemic areas the prevalence of skin test result positivity increases with age and the incidence of clinical disease decreases with age, indicating that immunity is acquired in the population over time.

7. Clinical features kala-azar typically affects children less than 5 yr of age. After inoculation of the organism into the skin by the sandfly, the child may have a completely ---->>>> 1- Asymptomatic infection : show no clinical evidence of disease. or 2- Oligosymptomatic illness that either resolve or goes into active form Mild constitutional symptoms (malaise, intermittent diarrhea, poor activity tolerance) and intermittent fever. In most of these children the illness will resolve without therapy, but in approximately 25% it will evolve to active kala-azar within 2-8 months.

8. 3- Active Kala-azar: The classic clinical features of High fever, marked splenomegaly, hepatomegaly, and severe cachexia. Typically develop approximately 6 months after the onset of the illness, but a rapid clinical course over 1 month has been noted in up to 20% of patients. At the terminal stages: hepatosplenomegaly is massive, gross wasting, the pancytopenia is profound, and jaundice, edema, and ascites may be present. Bleeding episodes, especially epistaxis, are frequent. The late stage of the illness is often complicated by secondary bacterial infections, which frequently are the causes of death. Death occurs in >90% of patients without specific antileishmanial treatment. Clinical features (cont’d)

9. VL may also result from reactivation of a long-standing subclinical infection. A small percentage of patients previously treated for VL develop diffuse skin lesions, a condition known as post–kala-azar dermal leishmaniasis (PKDL). These lesions may appear during or shortly after therapy or up to several years later. The lesions of PKDL are hypopigmented, erythematous, or nodular and commonly involve the face and torso. They may persist for several months or for many years.

13. Diagnosis 1- Non specific: Anemia, thrombocytopenia, leucopenia, elevated hepatic transaminase levels, and hyperglobulinemia. 2- Specific: Serologic testing is very useful in VL because of the very high level of antileishmanial antibodies (IFAT, ELISA, LAT). An enzvme-linked immunosorbent assay using a recombinant antigen (K39) has a sensitivity and specificity for VL that is close to 100%. A negative serologic test result in an immunocompetent individual is strong evidence against a diagnosis of VL.

14. Diagnosis (cont’d) 3- Definitive diagnosis of leishmaniasis is established by the demonstration of amastigotes in tissue specimens or isolation of the organism by culture. In patients with VL, smears or cultures of material from splenic, bone marrow, or lymph node aspirations are usually diagnostic.

16. Differential diagnosis prolonged fever, cachexia, marked splenomegaly, hepatomegaly, Cytopenias. malaria, typhoid fever, brucellosis, infectious mononucleosis, leukemia.

18. Treatment All patients with VL should receive therapy. The pentavalent antimony compounds (sodium stibogluconate- Pentostam and meglumine antimoniate- Glucantime) have been the mainstay of antileishmanial chemotherapy for >40 yr. The recommended regimen is 20 mg/kg/day intravenously or intramuscularly for 28 days. An initial clinical response to therapy usually occurs in the 1st week of therapy but Complete clinical healing is usually not evident for weeks to a few months after completion of therapy.

19. Treatment (cont’d) Cure rates with this regimen of 80-100% for VL were common in the 1990s, but clinical resistance to antimony therapy has become common. Relapses are common in patients who do not have an effective antileishmanial cellular immune response. These patients often require multiple courses of therapy or a chronic suppressive regimen. When clinical relapses occur, they are usually evident within 2 mo after completion of therapy. Adverse effects of antimony therapy are dose and duration dependant: Fatigue, arthralgia and myalgias, Abdominal discomfort, elevated hepatic transaminase level, elevated amylase and lipase levels, Mild hematologic changes. Sudden death due to cardiac toxicity is extremely rare and associated with very high doses of antimony Rx.

20. Other therapies 1. Amphotericin B is very useful in the treatment of VL or ML, and in some regions used as 1 st line therapy. 2.Recombinant human interferon as an adjunct to antimony therapy in the treatment of refractory cases of VL. 3. Miltefosine, a membrane-activating phospholipid, has been developed as the 1st oral treatment for VL. 4. Paromomycin and Pentamidine.

22. Follow up Clinical 1- General condition (1 st week). 2- Body temperature (1 st week). 3- Liver and spleen size (weeks to months). Hematological 1- CBC (weeks to months). Serological 1- K39 assay 2- PCR

25. Black fever

26. Epstein Barr VirusEpstein Barr Virus

27. EBV is a gamma-type herpesvirus. The two major strains of EBV (EBV type-1 and -2) differ biologically and in their geographic and ethnic prevalences. Infectious mononucleosis is the best-known clinical syndrome caused by Epstein-Barr virus (EBV), originally described as glandular fever. Other pathogens may cause a mononucleosis-like illness like CMV, Toxoplasma, Hepatitis, Adenovirus and HIV. The age at first infection varies according to living conditions. Introduction

28. The virus is shed in the secretions (saliva and genital). The term “kissing disease” acknowledges the oral route by which most people are infected. Infection occurs at an earlier age in the presence of poor hygiene and crowded living conditions. EBV infects >95% of the world’s population. It is transmitted via penetrative sexual intercourse and in oral secretions such as “deep kissing” and sharing water bottles. It can also be transmitted by blood product transfusion and with bone marrow and solid organ transplantation. Introduction (cont’d)

29. Among children, transmission may occur by exchange of saliva from child to child, such as occurs between children in out-of-home child care. EBV is shed in oral secretions consistently for >6 mo after acute infection and then intermittently for life. Primary EBV infection in adolescents and adults manifests in >50% of cases as the classic triad fatigue, pharyngitis, and generalized lymphadenopathy, which constitute the major clinical manifestations of infectious mononucleosis. This syndrome may be seen at all ages but is rarely apparent in children 40 yr of age, of whom most individuals have already been infected by EBV. Epidemiology

30. Clinical Aspects Primary Infection Symptomatic acute EBV infection is recognized clinically as IM. The incubation period is 30-50 days. Shorter in children. The majority of cases of primary EBV infection in infants and young children are clinically silent. In older patients, the onset of illness is usually insidious and vague. Patients may complain of malaise, fatigue, acute or prolonged (>1 wk) fever, headache, sore throat, nausea, abdominal pain, and myalgia. This prodromal period may last 1-2 wk. The sore throat and fever gradually worsen until patients seek medical care.

31. Primary Infection The pharyngitis can vary from a mild erythema to a very painful throat that has a thick gray-white exudate. Petechiae at the junction of the hard and soft palate are frequently seen. The classic physical examination findings are generalized lymphadenopathy (90% of cases), splenomegaly (50% of cases), and hepatomegaly (10% of cases). Lymphadenopathy occurs most commonly in the cervical nodes and less commonly in the axillary and inguinal lymph nodes. Epitrochlear lymphadenopathy is particularly suggestive of infectious mononucleosis.

32. Clinical Aspects (cont’d) Splenomegaly to 2-3 cm below the costal margin is typical; massive enlargement is uncommon. Fatigue: A distinct fatigue syndrome is associated with IM, lasting about 8 weeks. Rash: Rashes are usually maculopapular and have been reported in 3- 15% of patients. Antibiotic administration, particularly of Ampicillin, has been linked to the subsequent development of rash in older patients who have IM (80%). This vasculitic rash is probably immune mediated and resolves without specific treatment.

37. Other consequences X-linked Lymphoproliferative Disease. Burkitt Lymphoma. Nasopharyngeal Carcinoma. Hodgkin Disease. T-cell Lymphoma. Gastric Carcinoma

38. Diagnostic Tests  Non specific tests: WBC: 10,000-20,000 cells/mm3, of which at least two thirds are lymphocytes; atypical lymphocytes usually account for 20-40% of the total number. Atypical lymphocytosis in acquired cytomegalovirus, toxoplasmosis, hepatitis, rubella, roseola, mumps, tuberculosis, typhoid, Mycoplasma, malaria, and drug reactions. PLT: 50,000-200,000 platelets/mm3 but only rarely is associated with purpura. Mild elevation of hepatic transaminase values occurs in approximately 50% of uncomplicated cases but is usually asymptomatic and not associated with jaundice

40. Diagnostic Tests (cont’d)  Specific tests: Epstein-Barr virus (EBV) infection induces specific antibodies to EBV and various unrelated non-EBV heterophile antibodies. 1. Specific Antibodies: VCA (IgM early and IgG late) and EBNA (late). 2. Heterophile Antibodies: These antibodies react to antigens from animal RBCs. Culture of EBV is tedious and requires 4-6 wk. ممل

44. Diagnostic Tests (cont’d) Documenting the presence of heterophile antibody virtually confirms acute EBV infection, and there usually is no reason for further diagnostic tests. A positive heterophile reaction is a desirable adjunct but not essential to the diagnosis Sheep RBCs agglutinate with heterophile antibodies: Paul-Bunnell test. Positive for months Horse RBCs on exposure to heterophile antibodies: Monospot test. Positive for up to 2 yrs. It detects 90% of cases in older children but in only up to 50% of cases in children <4 yr of age because of lower titer.

45. Complications Occur in about 20% of patients recently infected with EBV; Essentially no body system is free from potential harm. The respiratory, neurologic, and hematologic systems are involved most frequently. Airway obstruction can be life threatening and is the most common reason for hospital admission. EBV has been implicated in virtually every form of infection-related neurologic disorder.

46. Complications (cont’d) Auto reactive antibodies cause immune hemolytic anemia or immune thrombocytopenia. About 10% of preschool age children develop neutropenia. Generally, increased levels of Ig increase the propensity for immune complexes to be formed, which may account for other disease-associated features such as rash, myalgia, and arthralgia. Rare complications: pancreatitis, orchitis and parotitis.

47. Treatment  Resources to manage acute EBV infection and its complications remain limited.  “Take it easy” is a usual recommendation.  Contact sports and activities (i.e., bike riding)? Spleen?  Although steroids often are recommended for management of impending (1) airway obstruction or (2) severe thrombocytopenia, only anecdotal evidence supports their benefit.

48. Prognosis The prognosis for complete recovery is excellent. The major symptoms typically last 2-4 wk followed by gradual recovery. Prolonged and debilitating fatigue, malaise, and some disability that may wax and wane for several weeks to 6 mo are common complaints even in otherwise unremarkable cases. Occasional persistence of fatigue for a few years is well recognized.

49. Exudative Tonsillitis

52. Ampicillin rash

59. Thank you Live in peace, not in pieces