5 ذو الحجة 1434 هـ Pediatric Lec. by Dr. Nadhim
10/10/2013
FEVER AND HEPATOMEGALY
(AIDS AND KALA AZAR)
'' HIV DISEASE IN CHILDEN ''
The WHO estimates that approximately 2.3 million children are living with the human immunodeficiency virus (HIV) as of 2006.In 2006 alone, 530,000 children were newly infected, an improvement from the 640,000 newly infected in 2004.
This is most prevalent in sub-Saharan Africa, where 18 million children are predicted to be orphaned by AIDS by the end of 2010.
Worldwide, the United Nations Children's Fund (UNICEF) predicts the number of children orphaned and made vulnerable by HIV/AIDS is expected to reach 25 million by the end of the decade.
HIV infection in children progresses more rapidly than in adults, and some untreated children die within the 1st 2 yr of life (higher viral burden and faster depletion of infected CD4 lymphocytes).
ETIOLOGY & PATHOGENESIS :
HIV-1 and HIV-2 are members of the Retroviridae family and belong to the Lentivirus genus, which includes cytopathic viruses causing diverse diseases in several animal species.The HIV-1 genome contains 2 copies of single-stranded RNA. Although 2 strains of HIV have currently been identified, most patients who have AIDS are positive for HIV type 1 (HIV-1) or are positive for both HIV-1 and HIV type 2 (HIV-2).
HIV-1 is a retrovirus that exhibits a variety of structural and nonstructural proteins that determine the interaction of the virus with the host's immune system and cellular components. The HIV virus attaches to the host cell by the association of a surface glycoprotein to the CD4 molecule; therefore, it primarily infects CD4+ lymphocytes and macrophages. Once the virus core enters the cell cytoplasm of the host, viral reverse transcriptase copies viral RNA to the DNA of the host.
The viral DNA is then transported into the nucleus and incorporated into the DNA of that cell. If activated, viral expression can result in new viral RNA and proteins. New viral core proteins, enzymes, and viral RNA molecules can induce budding, with additional cell infection.
The reduction in cell-mediated immunity and secondary B-cell dysfunction result in the immunocompromised state and in the proliferation of opportunistic infections and malignancies. An elevated level of activation-induced cell death resulting from apoptosis of T cells occurs in patients who are HIV positive.
EPIDEMIOLOGY :
An estimated 2.3 million children worldwide younger than15 years are living with HIV/AIDS. As of 2007, 90% of the newly infected children are infants who acquire HIV from their infected mothers.
A vanishing minority of children were infected through receipt of contaminated blood products and/or clotting factors, primarily before 1985, when screening of the blood supply was instituted.
Alarmingly, 90% of babies who acquire the disease from infected mothers are found in sub-Saharan Africa. The prevalence of HIV infection among undernourished children has been estimated to be as high as 25%.
In 2004, more than half a million children younger than 15 years died from HIV/AIDS. In 2006, this number decreased to 380,000. In 2002, HIV/AIDS was the seventh leading cause of mortality in children in developing countries.
Transmission :
Transmission of HIV-1 occurs via sexual contact, parenteral exposure to blood, or vertical transmission from mother to child. The primary route of infection in the pediatric population is vertical transmission, accounting for almost all new cases. Rates of transmission of HIV from mother to child varied among countries. Vertical transmission of HIV can occurbefore (intrauterine), during (intrapartum), or after delivery (through breast-feeding). Intrauterine transmission has been suggested by identification of HIV by culture or polymerase chain reaction (PCR) in fetal tissue as early as 10 wk.
It is generally accepted that 30-40% of infected newborns are infected in utero, because this percentage of infants has laboratory evidence of infection (positive viral culture or PCR) within the 1st wk of life.
The highest percentage of HIV-infected children acquire the virus intrapartum (exposure to infected blood and cervicovaginal secretions in the birth canal, where HIV is found in high titers during late gestation and delivery), evidenced by the fact that 60-70% of infected infants do not demonstrate detectable virus before 1 wk of age. breast-feeding is an important transmission route in developing countries.
WHO Clinical Staging of HIV/AIDS for Children with Confirmed HIV Infection:
@CLINICAL STAGE 1- Asymptomatic
- Persistent generalized lymphadenopathy
@CLINICAL STAGE 2
- Unexplained persistent hepatosplenomegaly - Papular pruritic eruptions- Fungal nail infection - Angular cheilitis
- Lineal gingival Erythema - Extensive wart virus infection
- Extensive molluscum contagiosum - Recurrent oral ulceration
- Unexplained persistent parotid enlargement - Herpes zoster
- Recurrent or chronic upper respiratory tract infections (otitis media, otorrhoea, sinusitis, tonsillitis).
@CLINICAL STAGE 3
- Unexplained moderate malnutrition or wasting not adequately responding to standard therapy
- Unexplained persistent diarrhea (14 days or more)
- Unexplained persistent fever (above 37.5°C intermittent or constant, for longer than one month)
- Persistent oral candidiasis (after first 6–8 weeks of life)
- Oral hairy leukoplakia
- Acute necrotizing ulcerative gingivitis or periodontitis - Lymph node tuberculosis
- Pulmonary tuberculosis - Severe recurrent bacterial pneumonia
- Symptomatic lymphoid interstitial pneumonitis
- Chronic HIV-associated lung disease including brochiectasis
- Unexplained anemia (<8 g/dl), neutropaenia (<0.5 × 109 per litre) or chronic thrombocytopenia (<50 × 109 per litre).
@CLINICAL STAGE 4
Unexplained severe wasting, stunting or severe malnutrition not responding to standard therapy
Pneumocystis pneumonia
Recurrent severe bacterial infections (such as empyema, bone or joint infection or meningitis but excluding pneumonia)
Chronic herpes simplex infection (orolabial or cutaneous of more than one month’s duration or visceral at any site)
Esophageal candidiasis (or of trachea, bronchi or lungs)
Extrapulmonary / disseminated tuberculosis
Kaposi’s sarcoma
Cytomegalovirus infection: retinitis or cytomegalovirus infection affecting another organ, with onset at age older than one month
Extrapulmonary cryptococcosis (including meningitis)
Central nervous system toxoplasmosis (after one month of life)
HIV encephalopathy
Disseminated endemic mycosis (extrapulmonary histoplasmosis, coccidiomycosis)
Disseminated non-tuberculous mycobacterial infection
Chronic cryptosporidiosis (with diarrhea)
Chronic isosporiasis
HIV associated tumors including Cerebral or B-cell non-Hodgkin lymphoma
Progressive multifocal leukoencephalopathy
Symptomatic HIV-associated nephropathy or cardiomyopathy.
Laboratory diagnosis :
HIV DNA PCR Preferred test to diagnose HIV-1 infection in infants and children younger than 18 mo of age; highly sensitive and specific by 2 wk of age and available; performed on peripheral blood mononuclear cells.
HIV p24 Ag Less sensitive, false-positive results during 1 mo of Iife,variable results; not recommended
HIV culture Expensive, not easily available, requires up to 4 wk to do test; not recommended
HIV RNA PCR Not recommended for routine testing of infants and children younger than 18 mo of age because a negative result cannot be used to exclude HIV infection definitively
Antibody to HIV In children ≥18 months of age, antibody testing should be done in the same manner as in adults. Detected by EIA, immunoblot, or immunoflurescent techniques..
%CD4 and lymphocyte count.
WHO Case Definition for HIV Infection in Children Diagnosis of HIV infection is based on laboratory criteria :
Children younger than 18 months:
• positive virological test for HIV or its components (HIV-RNA or HIV-DNA or ultrasensitive HIV p24 antigen) confirmed by a second virological test obtained from a separate determination taken more than four weeks after
birth. Positive antibody testing is not recommended for definitive or confirmatory diagnosis of HIV infection in children until 18 months of age.
Children 18 months or older:
• positive HIV antibody testing (rapid or laboratory-based enzyme immunoassay). This is usually confirmed by a second HIV antibody test (rapid or laboratory-based enzyme immunoassay) relying on different antigens or of different operating characteristics• OR
• positive virological test for HIV or its components (HIV-RNA or HIV-DNA or ultrasensitive HIV p24 antigen) confirmed by a second virological test obtained from a separate determination.
WHO Case Definition of AIDS in Children AIDS is defined clinically or immunologically in children with confirmed HIV infection
Confirmed HIV infection AND clinical diagnosis (presumptive or definitive) of any stage 4 condition
• OR
Confirmed HIV Infection AND first ever documented:
• %CD4+ <25 among infants younger than 12 months of age
• %CD4+ <20 among children aged 12-35 months
• %CD4+ <15 among children aged 36-59 months
• CD4 cell count of less than 200/ mm3 or % CD4+ <15 among children 5 years or older
AIDS case reporting for surveillance is no longer required if HIV infection or advanced HIV infection is reported.
TREATMENT: specific, supportive
Specific:
The currently available therapy does not eradicate the virus and cure the patient; it only suppresses the virus for extended periods of time and changes the course of the disease to a chronic process. Decisions about anti-retroviral therapy for pediatric HIV-infected patients are based on the magnitude of viral replication (viral load), CD4 lymphocyte count or percentage, and clinical condition.
Anti-retroviral drugs are categorized by their mechanism of action, such as the ability to inhibit the HIV reverse transcriptase or protease enzymes.
Within the reverse transcriptase inhibitors, further subdivision can be made:
1. nucleoside (or nucleotide) reverse transcriptase inhibitors (zidovudine, lamivudine ) and
2. non-nucleoside reverse transcriptase inhibitors (nevirapine, efavirenz).
3. The protease inhibitors (lopinavir, nelfinavir).
Supportive Care:
A multidisciplinary team approach is desirable for successful management. Close attention should be paid to nutrition, oral hygiene, development, and pain management.All HIV-exposed and infected children should receive standard pediatric immunizations. In general, live oral polio vaccine and live bacterial vaccines (BCG) should not be given. Neither varicella nor MMR vaccines are recommended to severely immunocompromised children.
Prophylactic regimens are integral for the care of HIV-infected children. All infants between 6 wk and 1 yr of age who are proven to be HIV infected should receive prophylaxis (e.g. TMP/SMZ, IVIG).
All HIV-exposed children should have skin testing (5TU PPD) for T.B. at 1 yr of age and be retested every 2 yr.
PROGNOSIS :
In general, the best prognostic indicators are the sustained suppression of plasma viral load and CD4' lymphocytes. A high viral load (>100,000 copies/mL) over time is associated with greater risk for disease progression and death. CD4 lymphocyte percentage is another prognostic indicator, and the mortality rate is higher in patients with a CD4 lymphocyte percentage of <I5%.Children with opportunistic infections, encephalopathy, or wasting syndrome have the worst prognosis. Persistent fever and/or oral thrush, serious bacterial infections (meningitis, pneumonia, sepsis), hepatitis, persistent anemia and/or thrombocytopenia also suggest a poor outcome.
In contrast, lymphadenopathy, splenomegaly, hepatomegaly, lymphoid interstitial pneumonitis, and parotitis are indicators of a better prognosis.
PREVENTION:
Interruption of perinatal transmission from mother to child has been achieved by administering ZDV chemoprophylaxis to the pregnant woman (started as early as 4 wk of gestation) and continued during delivery and in the newborn for the 1st 6 wk of life.
Educational efforts about avoidance of risk factors are essential for older school-aged children and adolescents.
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"أعجب وأشفق على هؤلاء الذين ما أن حدثتهم في أي شيئ حتى بدءوا بالتباكي وتصنع المسكنة و تصنع الجهل في خصوص الموضوع الذي تحدثهم فيه ،إعتقادا منهم أن هذا يبعد عنهم العين والحسد و كأنهم قد بلغوا الجوزاء بإنجازاتهموأعتقد أن هؤلاء هم من صنف الناس الذين لم يروا نعيما و صار عندهم شيئ قليل فرأوا أنهم ملكوا الدنيا وما فيها (بالعامية ما شاف...وشاف)
أو لم يعلموا ان الحمد لله شكر لنعمته ،
هم فقط يحفظون أن العين حق لكنهم ينسون أن الصدق صفة المسلم الحق فعلام ذلك التباكي, لا أدري ولست أبالي بأن أعرف،
طالما أن الناس إذا أجتمعوا على أن ينفعوك بشيئ فلن ينفعوك إلا بشيئ قد كتبه الله لك, و لو أجتمعوا على أن يضروك فلن يضروك إلا بشيئ قد كتبه الله عليك, رفعت الأقلام وجفت الصحف, أو كما قال المصطفى صلى الله عليه وسلم"
Visceral Leishmaniasis
(KALA AZAR)Leishmaniasis is a zoonotic infection caused by protozoa that belong to the genus Leishmania. transmitted by sandflies (Phlebotomus species). In the human host, Leishmania are intracellular parasites that infect the mononuclear phagocytes.
Epidemiology
The Leishmania species that infect humans are mainly leishmania donovani, which causes visceral leishmaniasis (kala azar).Geographical distribution of leishmaniasis is restricted to tropical and temperate regions (natural habitat of the sandfly). Leishmaniases are considered endemic in 88 countries (16 developed countries, 72 developing countries) on 5 continents: Africa, Asia, Europe, North America, and South America. A total of 350 million people are at risk. The incidence of leishmaniasis is increasing, mainly because of man-made environmental changes that increase human exposure to the sandfly vector. Poverty and malnutrition play a major role in the increased susceptibility to the disease. The immune deficiency has lead to increased susceptibility to infections, including leishmaniasis (AIDS). Another risk factor is the movement of susceptible populations into endemic areas, including large-scale migration of populations for economic reasons. The predominant mode of transmission is a sandfly bite which act as vectors. Uncommon modes of transmission include congenital transmission, blood transfusion, and, rarely, inoculation of cultures.
Pathophysiology
Leishmaniasis infections are considered zoonotic diseases because the infection is maintained in dogs, wild rodents, and other animals in endemic areas. Leishmania are obligatory intracellular parasites and are transmitted by the bite of the sandfly belonging to the genera Phlebotomus .Life cycle:
The parasite has 2 forms: the amastigote form and the promastigote form. The amastigote form occurs in humans, whereas the promastigote form occurs in the vector (sandfly). Only the female sandfly transmits the protozoan, infecting itself with the Leishmania parasites contained in the blood it sucks from its human or mammalian host. The parasite continues its development inside the sandfly into the promastigote form.
Following the bite, some of the flagellates (promastigote ) enter the cells of the reticuloendothelial system, where they change into the amastigote form. The amastigote forms also multiply. The multiplication continues until the host cell is packed with the parasites and ruptures, liberating the amastigotes into the circulation. The free amastigotes then invade fresh cells, thus repeating the cycle and, in the process, infecting the entire reticuloendothelial system. Some of the free amastigotes are drawn by the sandfly during its blood meal, thus completing the cycle.
CLINICAL FEATURES
The spectrum of illness ranges from asymptomatic infection to severe life-threatening infection. The disease is also known as kala azar, Dumdum fever, Assam fever, and infantile splenomegaly. It is the most severe form of leishmaniasis and is usually fatal within 2 years if left untreated. The incubation period is usually 3-6 months but can be months or years. Young malnourished children are most susceptible to developing progressive infection.The disease has an insidious onset with pyrexia(continuous or remittent ) which becomes intermittent at a later stage. It is characteristically described as a double rise in 24 hours. Waves of pyrexia may be followed by a period without fever. Children presenting later in the course of the disease may present with edema, hemorrhage, or growth failure.
The skin is dry, thin, and scaly, and hair is lost. As the disease progresses, the skin on the hands, feet, abdomen and face may become darkened, which is why the disease is also termed kala azar or black fever. Petechiae and ecchymosis may be seen in the extremities. Fulminant forms of visceral leishmaniasis is manifested by features that include pancytopenia and hepatic failure.
Splenic enlargement is a striking feature that is often considerable. Hepatomegaly and Lymphadenopathy are associated findings. Jaundice with mildly elevated enzyme levels is rarely seen and is considered a bad prognostic sign. Anemia is almost always present and is usually severe. Leucopenia is also observed and may contribute to secondary
infections. Thrombocytopenia contributes to the hemorrhagic tendency observed in some cases.
Hypergammaglobinemia, circulating immune complexes, and rheumatoid factors are present in sera of most patients with visceral leishmaniasis.
If untreated, death occurs within 2 years and is often caused by bacterial pneumonia, septicemia, dysentery, tuberculosis, cancrum oris, and uncontrolled hemorrhage or its sequelae.
Differential diagnosis
Visceral leishmaniasis - Includes other conditions associated with massive splenomegaly, including malaria, tropical splenomegaly syndrome, typhoid, miliary tuberculosis, portal hypertension, leukemia and lymphomas, hemolytic anemia .Lab Studies:
• Direct evidence of infection: The parasite can be detected through direct evidence from peripheral blood, bone marrow, or splenic aspirates, as explained below.• Indirect evidence of infection
*Detection of hypergammaglobinemia by aldehyde and the antimony tests.
*Immunological tests The direct agglutination test, which detects the specific immunoglobulin M (IgM) antibody at an early stage, has been found to be useful in the detection of both clinical and subclinical infections.
* Nonspecific tests: The direct agglutination test, immunofluorescent antibody test, complement fixation, and counterimmunoelectrophoresis are the various tests used in diagnosis of kala azar. Polymerase chain reaction (PCR) has also been used in the diagnosis of leishmaniasis. An immunochromatographic test for detection of anti–rK-39 antibodies has been reported with high sensitivity and specificity in diagnosis of visceral leishmaniasis. Leishmanin skin test (Montenegro test) is useful only for epidemiological purposes, indicating prior exposure to infection.
• Supportive tests: Hematological parameters include : a normochromic normocytic anemia, leucopenia, neutropenia, thrombocytopenia, elevated gamma globulin levels, and a reversal of the albumin/globulin.
TREATMENT :
Sodium stibogluconate, a pentavalent antimonial compound is the drug of choice in the treatment of visceral leishmaniasis. The dose 20 mg/kg/d IV/IM for 28 days. meglumine antimonate is also used. The earliest sign of improvement is an improvement in symptoms. Regression of splenomegaly takes a few months.
Supportive treatment includes rest, blood transfusions, and treatment of secondary infections.
A high-protein and high-calorie diet is required during the course of treatment.
Liposomal amphotericin B, Pentamidine, paromomycin, Ketoconazole, Itraconazole, Allopurinol, Interferon gamma, and miltefosine( the first oral antileishmanial agent licensed for use) are other alternatives used in treatment especially in resistant cases.