ACUTE SEVERE ASTHMA

Dr. Magda El Seify

Professor of Pediatrics

Ain-Shams University

DEFINITION

  Acute severe asthma / Near fatal asthma / Status asthmaticus are progressively worsening attacks unresponsive to conventional therapy, requiring hospitalization.

Curr Opin Pulm Med. 2007 Jan;13(1)

OUTCOME

  About 30% of these episodes need admission to PICU with a mortality of 8%. Relapse rates vary from 7 to 15% depending on how well the patient is managed.

 Curr Opin Pulm Med. 2007 Jan;13(1)

ACUTE SEVERE ASTHMA

          Mechanism.

          Risk Factors.

          Features.

          Treatment Dilemma
 

Treatment Dilemma

          Air Driven Versus Oxygen Driven Nebulization Of  Beta 2 Agonists.

          Inhaled Beta-adrenergic Agonists

        How frequent?

        Continuous versus intermittent.

          Parenteral Beta Agonists when to use?

          Inhaled Anticholinergic Agents

          Corticosteroids In Acute Severe Asthma Parentral, Oral Or Nebulized?

          IV Aminophylline.

          Magnesium Sulfate

          Heliox In Acute Asthma

          Inhaled Nitric Oxide

CONCLUSION
   Despite many advances in the treatment of asthma and more effective ways of delivering bronchodilators in acute severe asthma, asthma remains the most common medical emergency in children.

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Relationship of Viral Infections to Wheezing Illnesses and Asthma 

            Mona Mostafa El Falaki

Professor of Pediatrics

Head of the Pediatric Allergy and Pulmonology Unit

Cairo University

 Viral respiratory infections are the major cause of acute wheezing illnesses in childhood. Not only are they an important source of morbidity and mortality but also foreshadow an increased risk of recurrent wheezing and the inception of the asthmatic phenotype. Practically all children contract viral respiratory infection, why do some wheeze and others not, is the subject of interest and controversy. Identification of risk factors influencing the outcome of viral respiratory infections in infancy and early childhood allows for the early recognition of at risk children and for the planning of preventive and therapeutic interventions.

A bidirectional interaction between host lung and/or immune developmental factors and viral factors probably determine the severity and long term consequences of these infections .The effects of an acute inflammatory response to viral lower respiratory tract infections are age dependent and infancy represents a period of great vulnerability because it is a period of rapid growth and development of the lung and airways. Airway specific factors, such as pre-existing airway hyper-responsiveness, limitations to airflow, or both, increase the risk of recurrent wheezing after exposure to viruses. The host’s immune response plays a critical mechanistic role through the production of certain cytokines and chemokines. Children with detectable IFNγ at birth are less likely to wheeze. The influence of viral infections on the risk of recurrent wheezing appears to wane with age.

 Epidemiologic studies have mainly focused on the association of respiratory syncytial virus (RSV) infections in early life with the subsequent development of wheezing and/ or asthma, however,  the introduction of modern molecular PCR based techniques for viral identification have highlighted the contribution of other viral species. Although human metapneumovirus, influenza, and parainfluenza are all associated with episodes of wheezing, it appears that human rhinovirus infections contribute more substantially to asthma development than was previously appreciated. Not only has it been reported that children hospitalized with rhinovirus-induced bronchiolitis are at particularly high risk for subsequent development of asthma, but ,in a recent study, rhinovirus-induced lower respiratory illness during infancy was the single most significant risk factor for subsequent development of childhood asthma.

      Infection of lower airway epithelium ,viral latency and persistence in lung tissues, recruitment of  inflammatory cells into the airways and induction of pro-inflammatory cytokines (TNF-α, IL-1, IFN-γ, IL-6, IL-8), chemokines (MIP-1, RANTES), and adhesion molecules (ICAM-1) from airway resident and inflammatory cells are some of the mechanisms involved in viral associated wheezing. Viral infections can induce the synthesis of many of the factors that regulate airway and alveolar development and remodeling including NO, TGF-β, and FGF. The possible impact of these growth factors on the ultimate lung structure and function is still not known.

  The preventive and therapeutic options available for the control of childhood wheezing associated with viral infections are less than ideal. Proposed strategies include:

   Antiviral approaches

Ø      Vaccination: influenza vaccine, ? RSV, ? RV.

Ø      Monoclonal neutralizing antibodies to RSV, Palivizomab.

Ø      Antiviral medications: influenza neuraminidase inhibitors.

Ø      Soluble ICAM-1 derivatives & VLDL receptor fragments.

Ø      Macrolide antibiotics, bafilomycin A1 & erythromycin inhibit ICAM-1 epithelial expression.

Ø      Preventing uncoating of picornavirus.

Ø      Agents interfering with viral enzymes e.g. RV 3C protease.

Anti-inflammatory approaches

Ø       Glucocorticoids show poor efficacy in models of human experimental infection.

Ø      Intermittent ICS therapy in infants and young children with virus induced wheezing does not reduce overall symptom burden nor decrease the incidence of developing asthma.

Ø      Recently, in vitro ICS/LABA was able to suppress pro-inflammatory mediators in RV-infected bronchial epithelial cells.

Ø      Leukotriene receptor antagonists showed a small but significant inhibition of postbronchiolitis lower airway symptoms. Moreover, montelukast reduced the number of virally induced asthma exacerbations in young children with intermittent asthma.

     To conclude, respiratory viral infection occurring in a genetically susceptible host at a critical time period in either the development of the immune system or the lung is a risk factor for the inception of the asthmatic phenotype.

For further readings:   

§           Gern JE, Brooks GD, Meyer P,Chang A, et al. J Allergy Clin Immunol 2006;117:72-78.

§           Gern JE, Rosenthal LA, Sorkness RL, Lemanske RF Jr. J Allergy Clin Immunol 2005:115:668-674.

§           Bossios A, Papadopaoulos NG. Breath 2006; 3:50-58.

§           Heymann PW, Carper HT, Murphy DD, Platts-Mills TAE, et al. 2004;114:239-247.

§           Kristjansson S, Bjarnarson SP, Wennergren G, Palsdottir AH, et al. 2005;116:805-811.

§           Lemanske RFJr, Jackson DJ, Gangnon RE,Evans MD, et al. J Allergy Clin Immunol 2005; 116:571-577.

§           Bisgaard H,Hermansen MN, Loland L,Halkjaer LB, et al.N Engl J Med 2006;354:1998-2005.

§           Bisgaard H. Am J Respir Crit Care Med 2003; 167:379-383.

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Familial Mediterranean Fever

Elham Hossny

Professor of Pediatrics, Ain Shams University

 Definition

Familial Mediterranean fever (FMF) is mainly an autosomal recessive disorder characterized by recurrent attacks of fever and serositis accompanied by pain. Amyloidosis with renal failure is a complication and may develop without overt crises (French FMF Consortium, 1997).

 Types of FMF

·        FMF type 1 is characterized by recurrent short episodes of inflammation and serositis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family.

·        FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual.

 Pathogenesis

·        FMF is caused by mutations in the MEFV (Mediterranean fever) gene present on the short arm of chromosome 16.

·        This gene produces a protein called pyrin (derived from the association with predominant fever) or marenostrin derived from the phrase "our sea," because of the Mediterranean heritage of most patients.

Epidemiology

·        The disease occurs in ethnic groups originating in the Mediterranean area, mainly in Sephardic Jews, Arabs, Turks and Armenians.   Globalization in recent years has led to a rise of cross-border migration in Europe and the United States, which has led to a steady increase of the foreign population in many countries and FMF can therefore be encountered in many countries away from the Mediterranean.

·        Sex: in adults, FMF is more prevalent in men than in women, with a male-to-female ratio of 1.8:1.

·        Age: of all persons with FMF, 60% are younger than 10 years, 90% are younger than 20 years, and 5-10% are older than 20 years. The onset may be as early as 6 months of age. FMF very rarely starts in persons older than 40 years.

The Criteria for Diagnosis FMF

·        Major Signs

−        Fever

−        Abdominal pain

−        Chest pain

−        Joint pain

−        Skin eruption

·        Minor Signs

−        Increased erythrocyte sedimentation rate

−        Leukocytosis

−        Elevated serum concentration of fibrinogen (Normal: 200-400 mg/dL).  

       The minimal criteria for diagnosis are fever plus one more major

    and one minor sign, or fever plus two minor signs.

   (Shohat M. FMF. Cited in: Gene Reviews. http://www.genetests.org)

 Differential Diagnosis

Periodic Fever Syndromes (Auto-inflammatory Diseases):

·        PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome): < 5 yr

·        HIDS (hyperimmunoglobulinemia D and periodic fever syndrome): AR, European descent (Dutch & French). IgD > 100 U/mL

·        TRAPS (TNF receptor-associated periodic syndrome): AD, occurs in Scottish (also called familial Hybernian fever)

·        ELA-related neutropenia includes congenital neutropenia and cyclic neutropenia: AD

 Investigations

·        Genetic screening by restriction analysis PCR.

·        Because most of the known MEFV mutations (>90%) are in exon 10, most laboratories offer sequencing of this locus only.

·        However, less common mutations are thus missed.

·        Therefore, the diagnosis of FMF is still based on clinical grounds and genetic screening should be used as a confirmatory test.

 Prenatal Diagnosis

·        It is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis at about 15-18 weeks' gestation or chorionic villus sampling at 10-12 weeks' gestation.

·        Prenatal diagnosis of FMF, a treatable condition associated with a good prognosis with early treatment, may be controversial if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis.

 Treatment

·        Prophylactic colchicine therapy 0.02 – 0.03 mg/kg/day (max 2 mg/day) in 1 or 2 divided doses.

·        It does not only prevent acute attacks but decreases the probability of amyloidosis and may even lead to partial regression of existing amyloidosis.                   

Treatment of colchicine resistant cases

·        IV colchicine: 1 mg weekly in addition to daily oral colchicine therapy (Lidar et al, 2003).

·        Interferon alpha: 3-10 million I U SC as adjunctive therapy (Calguneri et al, 2004).

·        Thalidomide: (Seyahi et al, 2006).

·        Etanercept: 25 mg twice weekly but may lead to a severe injection site reaction (Seyahi et al, 2006).

 Further outpatient care

·        See patients regularly to ensure compliance with therapy.

·        Teenagers are typically a noncompliant group.

·        Perform a urinalysis at every visit. If proteinuria is present, assess for compliance and exclude other causes of proteinuria (e.g. heavy sports activity).

·        If proteinuria is confirmed, increase the daily dose of colchicine.

·        Hematuria occurs in approximately 5% of patients. Its presence, along with prolonged abdominal or muscle pain, suggests the development of polyarteritis nodosa.

 Medical/Legal Pitfalls

·        In patients with the appropriate ethnic background who present with what appears to be appendicitis or peritonitis, seek a family history of FMF to avoid an unnecessary laparotomy or appendectomy.

·        On the other hand, you should be alerted to the possibility of adhesive SBO or a coincidental acute appendicitis in patients with known FMF.

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Cell Therapy in Autoimmune Diseases

Prof. Shereen Reda

Professor of Pediatrics, Faculty of Medicine, Ain Shams University

Autoimmune diseases are a group of pathologic conditions caused by a breakdown of immune tolerance. The result is aberrant immune responses to self-antigens and the formation of autoantibodies. Attempts to dissect the complex pathogenesis of these diseases have indicated that T cells, B cells, innate immune system, pathogenic antibodies, complement and effector cells capable of recognizing the bound antibody can all have major & interweaving roles. Conventional immunosuppressive drugs are based on the systemic suppression of immune functions and are not curative. The auto-reactive cells are NOT specifically targeted.

New Therapies

Improvement in the use of immunosuppressants:

Mycophenolate mofetil (cellcept)

Tacrolimus

Leflunomide

Specific cell targeting (biologic response modifier)

•         Targeting APC

•         Targeting T cells

•         Targeting B cell & plasma cells

•         Blockage of co-stimulatory pathway

•         Generation of regulatory T cells (T regs)

•         Anti-cytokines

Immunoablation & BMT

Targeting APC

During the primary initiation of autoimmunity, APC are set in motion with uptake, processing and presentation of autoantigens to effector T cells. Blocking of costimulatory pathways such as CD80/86 could efficiently block primary activation of autoreactive T cells. However, the routine clinical use of soluble CTLA4-Ig is hampered due to their strong systemic side effects and altered protective immune responses necessary to shield the body against pathogens.

Targeting T cell

T helper cells can be targeted by monoclonal antibodies directed to CD4 molecule (keliximab). This will destroy autoreactive T cells as well as naïve (antigen inexperienced) T cells that deal with defense against foreign pathogens.

Targeting B Lymphocytes

B lymphocytes are responsible for humoral immunity. They provide a link between innate and adaptive immunity through antigen presentation, cell activation and production of cytokines. B cells are also the precursors of antibody-producing plasma cells.

In autoimmune diseases, B cells are important for the production and maintenance of autoantibodies to various self antigens. B-cell depletion will lead to removal of autoreactive B cells, suppression of antigen presentation to T cells and suppression of the release of pro-inflammatory cytokines by B cells (TNF-α & IL-6).

Targeting B cells can be achieved by:

1. Targeting B cell surface molecules (CD20, CD22 & CD19).  

2. Inhibition of co-stimulation pathway.

3. Inhibition of cell survival.        

4. Induction of B cell anergy (functional inactivation).

Several studies have proved efficacy of using of anti-CD20 Antibody (Rituximab) as a new therapy in various autoimmune diseases such RA, SLE, dermatomyositis, Wegener’s granulomatosis, Sjogren’s syndrome and antineutrophil cytoplasmic antibodies (ANCA) -associated vasculitis.

CO-stimulatory molecules

T cell offers help to B cell activation via two main co-stimulatory molecules, CD40/CD40ligand and B7/CD28. Monoclonal antibodies directed towards these two co-stimulatory pathway (anti-CD40L antibodies and CTLA4Ig) appears to be a promising therapeutic tool.

Tolerogens

These are synthetic molecules that bind to and crosslink the autoantibody surface receptor on B cell and trigger the signal transduction pathway that leads to B cell anergy and apoptosis.

Two B cell tolerogens have been used in human trials:

1.  (LJP394) induces tolerance to dsDNA in B cells.

2.  (LJP1082) induces tolerance to ß2-glycoprotein I in B cells.

Inhibition of B lymphocyte stimulating factor (BLyS)

B lymphocyte stimulator (BlyS) is a member of TNF family that is important for B cell survival and plasma cell proliferation. High BlyS levels were observed in the synovial fluid of RA patients as well as in the serum of SLE patients.

T regulatory cells (T regs)

Although negative selection prevents the exit of self reactive T cell clones to the periphery, some autoreactive T cells escape into the peripheral tissues. In healthy individuals, these autoreactive T cells are eliminated in the periphery by T regulatory (T reg) cells. In addition to preventing autoimmune responses by T cells, T reg cells control immune responses to foreign antigens. Because T reg cells are antigen specific, T reg cell manipulation represent the most natural way to treat autoimmunity.

Immunoablation & BMT

•         The only curative therapy.

•         HSCT is a treatment option for autoimmune diseases refractory to standard therapies.

•         Long term remission lasting for more than 6yrs without any treatment have been reported from different centers.

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    Difficulties in Childhood SLE Management

Professor Ashraf Abdel-Baqi

Professor of Pediatrics, Ain-Shams University.

Management Goals:

1- Induction of remission during disease flares.

2- Maintenance of remission inbetween disease flares.

3- Avoidance of serious organ damage.

4- Control of complications and adverse drug effects.

5- Maintenance of good general health.

The difficulties encountered in SLE management can be classified into:

• Difficulties in disease activity control.
• Difficulties related to the drug choice, dose, duration & side effects.
• Difficulties due to problems related to combined effect of the disease process and drugs adverse effects.

Obstacles in controlling disease activity:

The most frequent, serious  childhood SLE manifestation is lupus nephritis (LN) (up to 90%).

Problems in treatment of lupus nephritis:

·        Heterogeneity of disease expression (clinical & pathological).

·        Variability of clinical course.

·        Histological transformation.

·        Lack of consensus on outcome definitions, such as remission and relapse of LN.

·        Association with other serious disease manifestations ( Lupus cerebritis, Anti-Phospholipid antibodies syndrome).

Therapeutic difficulties:

§         Corticosteroids (CSD) are responsible of many disabling and even life-threatening complications in SLE patients. Moreover, an indefinite number of patients do not adhere to medical prescriptions mainly because of the esthetic side effects of corticosteroids. Corticosteroids, especially in high doses and long term therapy, produce hypertension, glucose intolerance, central obesity, and dyslipidaemia. Musculoskeletal side-effects include avascular necrosis, osteoporosis with fracture or vertebral body collapse, and even growth failure.

§         Choice of the proper immunosuppressant for steroid sparing effect and disease control is critical.

Combined disease & drugs induced problems:

• Infections particularly those associated with disease flares are challenging.
• Hypertension associated with the renal involvement and/or more commonly with CSD therapy, sometimes is difficult to control .
• Thrombocytopenia and anemia, direct disease effect and/or a product of bone marrow suppression by infections or cytotoxic drugs could be risky.

Strategy to overcome difficulties

^§          monitoring patients with regular urinalysis, measurement of blood pressure, and renal, lipid, and glucose profiles, especially in patients on corticosteroids. Early identification of disease flares is important.

^§           The treatment for individual patients varies and should be adjusted according to the clinical presentation and course of each patient. Hydroxychloroquine should be given to all patients with skin, joints or renal manifestations (3-7mg/kg/d). Non-steroidal anti-inflammatory drugs to be reserved to those with joint manifestations with no or mild renal affection. In general, oral administration of CSD to be prescribed initially to all patients with renal or CNS involvement, and immunosuppressive agents should be added in patients with significant renal proteinuria for the initial induction or maintenance as well as in those with significant neuropsychaitric and hematologic manifestations.

^§          The initial treatment modalities (induction) in the patients presenting with clinically severe LN, such as nephrotic syndrome, a deteriorating renal function, or a WHO class of grade III, IV or V, should be high-dose orally administered prednisolone (1–2 mg/kg per day, maximum 60 mg/day) for at least 1 month and/or intravenous injection of methylprednisolone (MPD) pulses (30 mg/kg per day, maximum 1 g/day) for three consecutive, with gradual tapering over the next 3–4 months to a maintenance dose of 0.25–0.5 mg/kg daily or on alternate days.

^§          Additional immunosuppressants should also included in the induction regimen in some patients who had severe LN as follows: 8 to 12 weeks of orally administered cyclophosphamide (CPM) at a daily dose of 1.5–2.5 mg/kg, or six courses of monthly intravenous injection of CPM pulse therapy. The CPM pulse therapy to be started at a dose of 500 mg/m² and increased to an augmented maximum dose of 1 g/m². 2-Mercaptoethane sulfonate sodium (MESNA) to follow each bolus CPM infusion in a dose equivalent to that of the CPM. The CPM dose to be reduced by 25%, or held at times in patients with decreased white blood cell (WBC) counts <4,000/mm³ 10–14 days after each bolus. Mycophenolate mofetil (MMF) can be an alternative in resistant cases (600 mg/m² PO bid). For maintenance therapy after completion of the initial induction, patients to be continued on CPM pulse therapy every 3 months for a total of 24–36 months, or to be treated with oral administration of immunosuppressants for various periods of time. These oral immunosuppressant regimes are mainly azathioprine (AZA) at a daily dose of 1–3 mg/kg,  or, MMF.

^§          For children with normal renal function and non-nephrotic proteinuria and/or class II or III LN as well for children with milder CNS or hematologic manifestations  a lower dose (0.5–1.0 mg/kg per day) of orally administered prednisolone alone should be maintained and tapered.

^§          When a disease flare, particularly renal occurs, a regimen similar to that of the induction therapy to be instituted.

^§          Intravenous immunoglobulins are increasingly being used in the treatment of resistant lupus. They also have a role in patients who have concomitant infection and active lupus, in whom immunosuppression is risky, although, the effect is usually short term.

^§          ACE inhibitors e.g.Enalapril should be prescribed to most patients with significant proteinuria, using various treatment courses. Symptomatic therapy consisted of antihypertensives, diuretics, vitamin D, calcium, anticoagulants and/or anti-platelet agents, to be given according to the clinical status of the patients.

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SELECTIVE IgA DEFICIENCY

Zeinab Awad

Professor of Pediatrics, Ain-Shams University.

Definition

Isolated absence or near absence of serum and secretory IgA associated with normal or elevated levels of IgG or IgM.

Pathogenesis

•      T cell defect: signal deficiency or suppressor T cells selectively inhibiting IgA production.

•      Inherent B cell defect

•      Failure of B cell terminal differentiation due to lack of effect caused by IL4, 6, 7, 10.

Inheritance

•      Mostly sporadic 

•      Familial (20%): AR, AD, multifactorial.

•      Genetically related to CVID

•      OMIM: IGAD1 gene map locus 6p21.3

Clinical Features (prevalence)

•      Allergic disorder (1/2)

•      Recurrent infections (1/2)

•      Autoimmunity (1/4)

•      Pulmonary fibrosis

•      MR and seizures

•      Fatal varicella

•      Coeliac disease

•      Malignancy

Infections

•      Recurrent sinopulmonary infections. Chronicity in 50%

•      Serious lung disease (pneumonia, bronchiectasis)

•      Diarrheas: viral, bacterial, G. lamblia

•      Viral hepatitis

GIT Manifestations

•      Milk intolerance

•      Nodular hyperplasia & malabsorption

•      Coeliac disease

•      Cystic fibrosis

•      Inflammatory bowel disease

Laboratory Workup

•      Serum IgA, G, M, E.

•      Serum IgG2, IgG4

•      IgG antibody response to vaccination

•      LN architecture is normal

•      Anti-IgA abs (IgG, IgE).

•      Investigations of the associated medical condition.

Diagnostic Criteria for IgAD

Definitive

•      Male or female

•      Greater than 4 years

•      Serum IgA of less than 7 mg/dl (0.07 g/L)

•      Normal serum IgG and IgM

•      Exclusion of hypogammaglobulinemia.

These patients have a normal IgG antibody response to vaccination.

 

Treatment

•      Pooled human IgA: not of much help.

•      Colostrum (oral) for GIT disease.

•      Prophylactic antibiotics.

•      Treat associated diseases.

•      Immunize with pneumococcal polysacch. v, H. infl. conjugate v.

•      Immunostimulatory extracts of multiple pathogens.

•      Transfer factor

•      Levamisole

•      BLyS proteins

•      IVIG: Carries the risk of adverse reactions (less with S.C.)

     Indications: - Combined IgA and IgG2 deficiency       - Severe infections

     Use: low IgA preparations, S.C.

For patients with anti-IgA antibodies:

•      Wear Medic alert bracelet.

•      Use, if indicated, only five times washed RBCs with 200 ml volumes or transfusions from another IgA deficient donor.

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