Tag Archives: Allergy/Immunology

Answer to CC #15

Case Challenge # 15 presented a 42-year-old white female with recurrent pneumonia in the setting of chronic dyspnea x 15 years without a determined etiology. She also has a history of COPD without smoking and recurrent sinus infections since childhood. She also notes chronic loose stools with occasional constipation for 10 years. Her mother also had COPD and recurrent sinus infections. Exam reveals no clubbing or nasal polyps.  CT chest reveals bronchial wall thickening and dilatation predominantly in the lower lung fields consistent with bronchiectasis.

Which of the following is the best initial test to establish the diagnosis?

CC 15(results of voting)

The correct answer is measurement of immunoglobulin levels!

The patient has CVID (common variable immunodeficiency)

  • CVID is a heterogeneous disorder characterized by markedly reduced serum concentrations of IgG, low levels of IgA and/or IgM, and poor or absent responses to immunization.
  • The disorder affects males and females equally, and usually has a later age of onset than other antibody-deficiency disorders (i.e., > 10 years of age).
  • It is associated with recurrent sinopulmonary infections, autoimmune and granulomatous disease, gastrointestinal complications and an enhanced risk of malignancy (e.g., lymphoma and gastric carcinoma).
  • Some patients may also present with bronchiectasis (irreversible widening of portions of the bronchi resulting from damage to the airway wall), which is a common cause of morbidity and mortality in these patients.
  • Ig replacement therapy is the mainstay of therapy for antibody-deficiency disorder
  • Antibiotic and antifungal prophylaxis are also recommended for some to prevent the frequency and severity of infections.

Case challenge #16 (aka the Parkland Files!) will be posted next week!

 

 

Allergy, Asthma & Clinical Immunology 2011, 7(Suppl 1):S11 . Published under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).

 

 

Eosinophilic Granulomatosis with Polyangiitis (EGPA) a.k.a Churg-Strauss Syndrome

Introduction

In 1951, Churg and Strauss described a syndrome with a relatively uniform clinical picture of severe asthma, fever, peripheral eosinophilia, and symptoms of “vascular embarrassment” in 13 patients initially diagnosed as having polyarteritis nodosa. Churg-Strauss syndrome (CSS) or Eosinophilic Granulomatosis with Polyangiitis (EGPA) is an uncommon form of antineutrophil cytoplasmic antibody-associated necrotizing vasculitis affecting the small-to-medium sized blood vessels. Disease typically follows three phases.

Etiology

  • Although the etiology of this disease is not well known, both T- and B-cell mediated immunity have been considered.
  • Hyper-responsiveness to antigenic stimuli may be the etiologic factor in the development of CSS.
  • In 1998, Wechsler and colleagues reported eight patients with this syndrome after a decrease or withdrawal of oral steroids.
  • Also cases have been attributed to antibiotics such as erythromycin, azithromycin and roxithomycin and some metered dose inhalers (bamuterol, salmeterol and nedrocromil)

Clinical Manifestations

  • The prodromal phase presents as adult-onset asthma, atopic disease, and allergic rhinosinusitis. It precedes the vasculitic phase by 3 to 9 years but intervals as long as 30 years have also been described.
  • Next, is the eosinophilic phase which is usually a subclinical eosinophilic tissue infiltration without necrosis but can sometimes manifest as pulmonary infiltrates or nodules with or without pneumonitis, or as gastroenteritis.
  • The third and final phase is the vasculitic phase, where patients are usually diagnosed. The mean age at presentation varies from 38 to 52 years of age, but can range from 7 to 74.
  • The most common manifestations at the time of diagnosis were asthma (91.1%), weight loss (49.3%), mononeuritis multiplex (46%), sinusitis or polyposis (41.8%), skin lesions (39.7%), and lung infiltrates (38.6%).

Diagnosis

  • Laboratory Studies
    • Eosinophilia usually appears in the second phase of disease, but can also initially present in the prodromal or vasculitic phases.
    • The presence of ANCA is documented in approximately 40% of EGPA and appears to be associated with renal and upper respiratory tract involvement, alveolar hemorrhage, purpura, biopsy-proven vasculitis and peripheral neuropathy.
      • The absence of ANCA is associated with pulmonary disease, cardiomyopathy, and fever.
      • The origin of this dichotomy is uncertain but it is hypothesized that the tissue damage in ANCA-negative EGPA is directly related to the presence of tissue eosinophils, whereas the ANCA-positive patients are thought to have endothelial damage in the typical ANCA-associated vasculitis fashion.
  • Criteria
    • In 1990, the American College of Rheumatology established the classification criteria for EGPA with a sensitivity of 85% and specificity of 99.7%.
    • Fulfillment of 4 or more criteria is needed for classification as EGPA.
      1. Asthma
      2. Eosinophilia greater than 10% on differential white blood cell count
      3. Mononeuropathy or polyneuropathy
      4. Migratory or transient pulmonary infiltrates detected radiographically
      5. Paranasal sinus abnormality
      6. Biopsy with perivascular eosinophils.
  • Imaging
    • The most common radiological findings are lobular or centrilobular peripheral consolidation and nodularity, thickened bronchial walls, inter-lobular septum, and peri-cardial and pleural effusion.
    • On computed tomography, enlargement of or distortion of peripheral pulmonary arteries may be seen.
  • Pathology
    • Histological diagnosis is by demonstration of vasculitis that is necrotizing, tissue infiltration with eosinophils and extra-vascular granulomas are found in a few cases

Differential Diagnosis

  • The differential diagnosis includes polyarteritits nodosa, Wegener’s granulomatosis, drug reaction, bronchogenic granulomatosis, fungal and parasitic infections, and malignancy

Treatment

  • Regularly with prednisone starting at 40-60 mg a day
  • Cyclophosphamide or azathioprine can be added with the purpose to limit the disease or spare steroids.
  • In case of fulminant disease or multi-organ involvement, parenteral corticosteroid such as methylprednisolone is used.
  • If response to mentioned treatment is not seen, parenteral immunoglobulin is administered.
  • Newly experimental medications for unresponsive cases are mycophenolate mofetil and tumor necrosis factor (TNF)-α blockers (such as etanercept and infliximab).
  • Treatment is continued at least one month after remission

Modified from:

– BMC Musculoskeletal Disorders 2014, 15:388

– Journal of Medical Case Reports 2010, 4:188

A New Approach in Reducing Risk of Peanut Allergy? Promising Study Released!

This week’s NEJM released a study (LEAP Trial) from King’s College in London looking at reducing the risk of developing peanut allergies in infants by having them consume peanuts. The authors observed decreased frequency of peanut allergies in the group that consumed peanuts versus the group that avoided. Dr. Rebecca Gruchalla, Professor and Director of the UT Southwestern Allergy and Immunology Division, co-wrote an editorial in the NEJM describing the trial and its potential effect on future studies and management of food-based allergies. Check out the original study and Dr. Gruchalla’s editorial below!

Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy

Preventing Peanut Allergy through Early Consumption – Ready for Prime Time? 

Acquired Angioedema

Summary

Acquired angioedema (AAE) is characterized by acquired deficiency of C1 inhibitor (C1-INH), hyperactivation of the classical pathway of human complement and angioedema symptoms mediated by bradykinin released by inappropriate activation of the contact-kinin system. Angioedema recurs at unpredictable intervals, lasts from two to five days and presents with edema of the skin (face, limbs, genitals), severe abdominal pain with edema of the gastrointestinal mucosa, life-threateing edema of the upper respiratory tract and edema of the oral mucosa and of the tongue. AAE recurs in association with various conditions and particularly with different forms of lymphoproliferative disorders. Neutralizing autoantibodies to C1-INH are present in the majority of patients. The therapeutic approach to a patient with AAE should first be aimed to avoid fatalities due to angioedema and then to avoid the disability caused be angioedema recurrences. Acute attacks can be treated with plasma-derived C1-INH, but some patients become non-responsive and in these patients the kallikrein inhibitor ecallantide and the bradykinin receptor antagonist icatibant can be effective. Angioedema prophylaxis is performed using antifibrinolytic agents and attenuated androgens with antifibrinolytic agents providing somewhat better results. Treatment of the associated disease can resolve AAE in some patients.

The symptoms

The three key elements of the syndrome commonly referred to as acquired angioedema (AAE), which was first described by Caldwell in 1972 [1], are acquired deficiency of C1 inhibitor (C1-INH), hyperactivation of the classical pathway of human complement and recurrent angioedema symptoms. It is considered a very rare condition with just more than 100 patients reported in the literature [2]. In absence of epidemiological data, we can only speculate about its prevalence. In our list of angioedema patients, we found 1 AAE for every 10 patients with the hereditary form of C1-INH deficiency (hereditary angioedema, HAE). HAE minimal prevalence in the population is 1.41/100,000 and usual estimated prevalence between 1:10,000 and 1:50,000 [3,4]. Therefore, a very crude estimated prevalence of AAE could range between 1:100,000 and 1:500,000. We believe that the actual number is much higher than this because the condition is frequently unrecognized.

From the clinical point of view the angioedema symptoms that characterize AAE can not be differentiated from those present in HAE patients who have a deficiency of C1-INH due to mutations in one of the two alleles coding for this protein [5]. This could be anticipated based on the fact that in both forms angioedema is mediated by bradykinin episodically released by inappropriate activation of the contact-kinin system lacking its major physiologic regulator C1-INH [6,7]. Thus, similar to HAE patients, patients with AAE have no major urticaria flare. Angioedema recurs at unpredictable intervals, lasting from two to five days and presenting with disfiguring, non pitting, non-pruritic edema of the skin (face, limbs, genitals), severe abdominal pain for edema of the gastrointestinal mucosa leading to temporary bowel occlusion (Figure 1) [8], life-threateing edema of the upper respiratory tract and edema of the oral mucosa and of the tongue [2]. The only significant clinical difference between HAE and AAE is the age of onset of symptoms (Table 1): within the second decade of life for more than 90% of patients with HAE, after the fourth decade for those with AAE. Some additional minor differences can be found looking at different rates of recurrences at specific sites. Angioedema of the gastrointestinal mucosa causing abdominal pain is reported by nearly 80% of patients with HAE while less than 50% of our AAE patients and around 30% of those from Bouillet et al [9] reported such symptoms. Nevertheless, presentation of AAE with abdominal symptoms has been reported in our series and in the literature [10]. Cutaneous angioedema in HAE patients is typically localized to the extremities. Even if this location is also present in patients with AAE, in them angioedema recurs more frequently in the face than in the limbs [9] and we also noticed a rather frequent involvement of tongue and uvula; (Figure 2).

AcqAE

The Pathogenesis

In the first patients reported by Caldwell [1], AAE occurred in presence of lymphoma. This association has been repeatedly confirmed in subsequent patients [1113] and even if lymphoma is not the only disease associated with AAE, it remains the preeminent disease association. Along with lymphoma, other benign forms of lymphoproliferation, namely monoclonal gammopathy of uncertain significance (MGUS), have been reported with high frequency in association with AAE. Capacity of lymphoma cells to deplete C1-INH or to cause its consumption through C1 activation, and the possibility to treat AAE by curing the underlying lymphoma, linked the lymphoproliferative disease to the pathogenesis of AAE [1,1115]. In 1985, neutralizing autoantibodies to C1-INH were described in a few otherwise healthy patients [16,17]. Anti-C1-INH autoantibodies recognize epitopes around the reactive center of C1-INH and by binding these epitopes render the protein functionally inactive and/or increase its catabolism [18,19]. Autoantibody-mediated AAE seemed to be, at the beginning, a new type of AAE in which autoreactive immunoglobulins, instead of lymphoma tissues, was the cause of C1-INH depletion [20]. Re-evaluation of existing and new AAE patients demonstrated that autoantibodies could be present along with lymphoma and that the M component detected in several AAE patients corresponded to the anti-C1-INH autoantibodies [21]. Based on these findings, we can now see AAE as a condition with different form of abnormal B cell proliferation progressing from autoreactivity to malignant lymphoma. Whether the different degrees of lymphoproliferation found in AAE patients are evolutionary stages of the same process starting from expansion of anti-C1-INH autoreactive clone(s) has not yet been clarified [22].

Although lymphoproliferative diseases represent the main group encountered in AAE and a direct pathogenetic relationship between the two conditions can not be questioned, SLE, different neoplasias and infections have also been described in association with AAE [2333]. The possibility chance association for some of these conditions can not be completely ruled out.

The Diagnosis

AAE is first suspected in patients aged 40 or above who present with recurrent cutaneous and/or mucosal angioedema without urticaria, without an evident triggering factor, and without family history of angioedema. Measurement of C1-INH and C4 antigen in such patients is the first step. If both are normal, the deficiency of C1-INH is very unlike. If both are low (with C1-INH below 50% of normal on two separate determinations) diagnosis of C1-INH deficiency is made. If just C4 is reduced, C1-INH functional activity needs to be determined and if low (below 50% of normal on two separate determinations) diagnosis of C1-INH deficiency is made. Once this diagnosis has been made, additional testing is necessary to distinguish between inherited and acquired deficiency. This testing includes determination of C1q which is reduced in 70% of patients with AAE and is normal in HAE. If C1q is reduced, diagnosis of AAE can be established. If C1q is normal, autoantibodies to C1-INH can be investigated and their presence at high titre allows diagnosing AAE. If antibodies are negative, the diagnosis of AAE is assumed when complete screening of C1-INH gene gives no evidence of mutations affecting C1-INH protein. Major limits to this procedure are the inadequate availability and standardization of C1-INH functional measurements [34] and the possibility to look for anti-C1-INH autoantibodies only in a few specialized research laboratories. Therefore, careful harmonization of clinical and laboratory findings is mandatory to establish the diagnosis of AAE.

Patients with this diagnosis should undergo basic testing for lymphoproliferative and autoimmune disease. In addition to complete physical exam, we suggest that all patients have laboratory testing for complete blood cell count with differential, serum protein electrophoresis, antinuclear antibodies, chest X ray and abdominal ultrasound assessing lymphoid tissue. Due to the limited recurrences of other associated diseases, we do not see the need to systematically screen for other neoplasia or infection without specific clinical indications.

The Treatment

The therapeutic approach to a patient with AAE should first be aimed to avoid fatalities due to angioedema and then to avoid the disability caused be angioedema recurrences. Angioedema- related fatalities derive from laryngeal edema. Based on the efficacy of replacement therapy with plasma-derived C1-INH in reverting laryngeal edema in patients with HAE [35], the same approach has been used for AAE. This treatment works in the majority but not in all AAE patients and in our experience some patient with AAE become progressively non responsive to plasma-derived C1-INH or need increased doses [5]. No other treatment for angioedema attacks has been extensively used in patients with AAE and therefore there is no established therapeutic alternative to plasma- derived C1-INH for life-threatening attacks. Non-responsive patients have just been assisted with invasive procedures aimed to maintain patency of upper airways during emergency. In recent years in a few AAE patients we have used two of the new treatments that have been proposed for HAE acute attacks: the kallikrein inhibitor ecallantide and the bradykinin B2 antagonist icatibant [36]. Since refractoriness to plasma-derived C1-INH is due to its autoantibody-mediated rapid catabolism, the use of drugs different from C1-INH but active in reversing HAE attacks have very good rationale for being effective in AAE. In fact from our limited experience response is extremely favourable. We treated 2 facial attacks in two patients with ecallantide and 1 laryngeal and 3 facial attacks in another patient with icatibant. Two of these patients were completely, and one partially, non-responsive to plasma derived C1-INH. All treated attacks responded very rapidly either to ecallantide or icatibant. The critical condition of C1-INH non-responder patients and the absence of licensed drugs strongly indicate the need for off-label treatments. Therefore, we recommend all our AAE patients always have 3000 U of plasma-derived C1-INH immediately available and treat attacks with 1500 U and repeating if ineffective. In the event of laryngeal edema, resuscitation facilities should be available. For those patients who have slow or no response, ecallantide or icatibant should be provided.

Reducing disability related to angioedema recurrences can be obtained by shortening attacks with an on-demand treatment with plasma-derived C1-INH, by preventing attacks with long term prevention with antifibrinolytics or androgens, or by curing the associated disease. The latter is the first choice when the associated disease has per se an indication to be treated. Resolution of the associated disease results in variable degrees of resolution of AAE from symptomatic improvement to complete biochemical and clinical recovery [1315]. Treatment of the associated disease aimed only to control angioedema symptoms requires careful risk/benefit evaluation. Since most of the time the associated disease is lymphoproliferative, the choice to start a patient on chemotherapy or immunosuppressant is not always straightforward. Long-term treatment to prevent angioedema symptoms is often used in HAE and has also been used in AAE. While in HAE androgen derivatives are very effective prophylactic agents, results may not be as good in AAE. The reason for this is not totally clear. We know that attenuated androgens can increase the plasma levels of C1-INH [37]. Even if effective androgen doses in HAE do not require a measurable increase of C1-INH in plasma, it is still possible that these drugs relay on C1-INH production and their efficacy is less when C1-INH catabolism is very rapid [38]. In contrast, antifibrinolytic agents, the other class of drugs used for symptom prophylaxis in HAE [39,40], seem to have better efficacy in AAE than in HAE. It is assumed that the effect of these drugs in C1-INH deficient patients works through their anti-plasmin activity. Plasmin is critical for angioedema symptoms in C1-INH deficiency although the role is not clearly defined [41]. In AAE patients, the instability of the systems controlled by C1-INH is higher than in HAE and active plasmin is also generated separate from angioedema symptoms reinforcing the rationale for efficacy of antifibrinolytics in this condition [4245]. At present, we consider antifibrinolytic agents as the first choice drug for angioedema prophylaxis in AAE. Prevention of attacks with continuous infusions of plasma-derived C1-INH has been attempted with controversial results and in our opinion having very little rationale [46,47]. The half life of plasma- derived C1-INH in HAE indicates two infusions per week as the minimum to maintain protective prophylactic plasma levels [48]. Even if one assumes that AAE patients will not require a more intensive program because of the faster C1-INH catabolism and will not increase the risk of becoming resistant to plasma-derived C1-INH, this prophylactic infusion regimen seems justified only for those patients with two or more severe attacks per week, a condition that we did not find in any of our 42 AAE patients. We reserve plasma-derived C1-INH infusions for on-demand treatment of severe angioedema events and do not use this for prophylaxis.

Allergy, Asthma & Clinical Immunology 2010, 6:14  doi:10.1186/1710-1492-6-14

The electronic version of this article is the complete one and can be found online at: http://www.aacijournal.com/content/6/1/14

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Answer to Case Challenge #4

Case challenge # 4 presented a 21 yo white male with recurrent fevers and joint pains. Symptoms started at age 10, episodes occur every 6 months. Fever episodes last about 2 weeks, also associated with periorbital edema and spreading rash on extremities. Father has similar symptoms and also developed renal failure and CHF in his 40s. On exam, he had a fever of 102.3 F, periorbital edema, patchy macular rash on extremities.

What is the most likely diagnosis in this case?

A) Familial Mediterranean Fever

B) TNF Receptor-1 associated periodic syndrome

C) Hyper IgD syndrome

D) Trichinosis

E) Cryopyrin-associated periodic syndromes

Here are the results of the voting:
Screen Shot 2015-02-20 at 9.57.49 AM
The patient has TNF Receptor-1 Associated Periodic Syndrome (TRAPS).
  • Autosomal dominant, one of periodic fever syndromes
  • First described in pt of Irish (Hibernian) origin
  • Due to genetic defect in TNF receptor gene (TNFR1)
  • Presents with fever of longer duration (5-20 days) plus abdominal pain, characteristic rash, conjunctivitis and periorbital edema
  • 25% develop amyloidosis with renal or cardiac dz.
Look forward to a more extensive review of TRAPS. There will be a new case challenge next week!

Anticonvulsant Hypersensitivity Syndrome

  • General Information
    • Drug-induced, multiorgan syndrome – potentially fatal.
    • Reported with anticonvulsants such as carbamazepine, phenytoin, phenobarbital and lamotrigine
    • Other medicines, such as sulphonamides, sulphones, allopurinol and NSAIDs
  • Clinical Diagnosis
    • Triad: fever, rash, and organ involvement (i.e. hepatitis)
      • Fever: 90-100% of cases – characteristically high, spiking fevers. May persist for weeks after the offending drug is discontinued. The fever may precede or be concurrent with the cutaneous eruption.
      • Rash: 90% of cases – typically macular erythema that becomes confluent and may generalize into erythroderma. The face, trunk and upper limbs are the first to be involved, followed by the lower limbs. The rash may spare the face. Desquamation occurs with resolution. Periorbital and facial edema may be severe and occurs in 25% of cases. Blistering may be seen over edematous areas.
      • Organ Involvement:
        • Hepatitis: 50% of cases – usually mild, but can be severe. The mortality rate is between 18 and 40% if hepatitis is present. Liver function tests may be grossly elevated and continue to rise after the drug has been discontinued. Return of liver function tests to normal may take up to a year.
        • Tender lymphadenopathy: occurs in 70% of cases and may be either local or generalized.
        • Splenomegaly: may also be seen, but is less common.
      • Hematologic abnormalities: 50% of cases – Leukocytosis with atypical lymphocytes and eosinophilia (only in 20%)  can be seen. Coagulopathy may also occur.
    • Each clinical feature may be of variable onset, leading to confusion and delay in diagnosis
    • Interval between first drug exposure and symptoms is usually 2-4 weeks, but has been reported in individuals receiving anticonvulsants for 3 months.
    • Syndrome is more severe in previously sensitized individuals.
  • Mechanism
    • Some features to suggest that it is a form of allergic hypersensitivity.
    • Phenytoin is metabolized by cytochrome P-450 to intermediate metabolites, known as arene oxides. Arene oxides can contribute to an immunological response or even cause cell death.
    • Usually detoxified by epoxide hydroxylase, but those who develop AHS may have decreased enzyme function.
  • Treatment
    • Treatment of AHS is largely symptomatic.
    • The offending medicine should be immediately discontinued.
    • Topical steroids and antihistamines are helpful in controlling symptoms associated with the rash.
    • Systemic corticosteroids are often used, although there have been no trials to assess the efficacy of this treatment.
    • Relapse of the condition is often seen; thus, patients who have experienced AHS should avoid arene oxide anticonvulsants (carbamazepine, phenytoin and phenobarbital) in the future.

Answer to Case Challenge #2

Case Challenge #2 presented a 42 yo female with fever, LAD, macular rash, and elevated LFTs after the recent intiation of phenytoin for new onset seizures.

CC2

What is the best management step?

D) Stop phenytoin – the patient has Anticonvulsant Hypersensitivity Syndrome

  • Starts within 2-4 weeks of starting anti-epileptics with aromatic benzene rings (subset of DRESS)
  • Main culprits: Carbamazepine, Phenytoin, Primidone, Phenobarbital
  • Stop drug and avoid repeat exposure to similar drugs
  • Buzz words: Rash, LAD, hepatitis, renal failure in person on offending agent
  • Eosinophilia only seen in about 20% of cases

Look forward to a more extensive review of Anticonvulsant Hypersensitivity Syndrome. There will be a new case challenge next week!