Case Challenge #5

  • HPI: A 28 yo female presents with fever and cervical LAD. She describes acute onset of fever and unilateral neck swelling. No sore throat, rash, or dental pain. She has a pet cat, but no history of scratches or bites.
  • Physical exam: Tmax 101.3, unilateral anterior and posterior cervical LAD. Otherwise unremarkable.
  • Labs: WBC 4k, 12% atypical lymphs. Monospot negative, EBV serologies consistent with prior exposure.
  • Imaging: CXR wnl
  • Lymph Node Biopsy: necrotizing lymphadenitis with histiocytes and nuclear debris, preserved architecture. Organism stains negative.

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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.

A Call to New Antibiotics Development!

Today in The New York Times, Dr. Ezekiel J. Emanuel (oncologist and vice provost at University of Pennsylvania), wrote an op-ed piece calling for a renewed focus and effort in the development of new antibiotics. He refers to recent outbreaks of multi-drug resistant organisms and possible reasons why developing new therapies has been lagging. Dr. Emanuel bring to attention the XPRIZE, a foundation that offers cash prizes for the development of new innovations that address unique problems, and offers a similar proposal. What if governments offered large cash prizes for the development of new antibiotics? Check out the op-ed piece as well as the XPRIZE website:

How to Develop New Antibiotics 

XPRIZE – Life Sciences Challenges

Medical Management of Frostbite

As the big winter chill continues, so does our series on cold-weather medicine!

Frostbite is a freezing, cold thermal injury, which occurs when tissues are exposed to temperatures below their freezing point (typically −0.55°C, but can occur as high as 2°C) for a sustained period of time [1].

Frostbiute1

Immediate and general care for those admitted with frostbite

On arrival to a hospital setting, it is vitally important to fully reassess the patient. Underlying unstable comorbidities, trauma or hypothermia must be assessed and managed before frostbitten extremities are treated. Moderate or severe hypothermia should be corrected to bring core temperature above 35°C before initiating frostbite warming [14,17] (recommendation grade 1C).

A detailed history should include time the injury occurred, either early (<24 h) or late (>24 h) as this will dictate some treatment options. History of the conditions surrounding the injury (i.e. temperature, wind chill, wet/dry exposure, duration and use or not use of thermal protection) can also be helpful. Any pre-hospital treatment and time of rewarming, if applicable, should be noted [14].

Remove jewellery from affected digits early as significant swelling can be expected post thaw, and vascular compromise may occur with tight rings, etc. [14]. Examination of the frostbitten tissue after rewarming can predict depth of injury more accurately than examination before thawing. There may be different depths of injury even on digits of the same extremity, so careful examination and documentation in either diagram form or with photographs are useful. Clinical photography obviates the need for repeated removal of dressings for each consultant examination, reducing pain and risk of infection. Loss of sensation after rewarming is a poor prognostic indicator, and the converse is also true.

Classification

There exist a number of frostbite classifications to assess the severity and predict likely outcome. Cauchy et al. have suggested a useful classification consisting of four grades and three key descriptors (Table 2) [18]. At 24 h post insult after rewarming, a grade can be attributed according to the level of any visible lesion. Then, at day two, a technetium99 triple-phase bone scan should be performed on the more severe injuries (see Imaging section) and a further assessment of any blisters undertaken. Injuries receiving grade 1 classification require no hospitalisation and full recovery is likely. Grades 2 through 4 injuries require hospitalisation and full investigation as they are associated with an increased risk of amputation and long-term sequelae [18].

FrostbiteClassification

Fluids

Rehydration can be oral or intravenous, and depending upon severity and ability of the patient to tolerate oral fluids. High altitude increases the risk of dehydration. If the patient is also hypothermic, dehydration may be compounded by cold diuresis due to suppression of antidiuretic hormone, requiring correction with warmed intravenous fluids (recommendation grade 1C).

Rewarming

Rewarming is beneficial if there remains a partially or fully frozen part and is ideally accomplished using a whirlpool bath set at 38°C with added antiseptic solution (povidone iodine or chlorhexidine). The Wilderness Medical Society and State of Alaska Cold Injury Guidelines recommend a temperature of 37°C–39°C, which decreases the pain experienced by the patient whilst only slightly slowing rewarming time [14,15]. The time period for optimal rewarming varies from 15–30 min up to 1 h [16]. Rewarming should continue until a red/purple colour appears and the extremity tissue becomes pliable [14]. Active motion during the rewarming process is beneficial, but care should be taken to prevent the extremity from touching the sides of the whirlpool. It is important to provide good analgesic cover and is likely to include narcotic medication (recommendation grade 1B).

Blisters and dressings

It is important to note the type of any blisters that form; they can be clear/cloudy or haemorrhagic in nature. There is current debate as to whether blisters should be de-roofed as this may desiccate the underlying tissue, but there is little comparative data to settle this argument. The recommended practice is that of selective drainage of clear/cloudy blisters by needle aspiration (especially if bullae restrict movement) and to leave haemorrhagic blisters alone [14]. However, we would suggest that all blisters are debrided in the hospital (not in the field) because we believe it assists with wound care. Severe injuries require detailed assessment, and it may be that this appraisal and debriding of blisters may be best performed under a general anaesthetic (recommendation grade 2C).

Topical aloe vera cream or gel (a potent anti-prostaglandin agent) should then be applied to thawed tissue before dressings are applied [14] (recommendation grade 2C). Splinting, elevating and wrapping the affected part in a loose, protective dressing with padding between affected patient’s digits are ideal (recommendation grade 1C).

Antibiotics

The role of prophylactic antibiotics is not proven but should be considered in more severe injuries (grades 3 and 4) and, in particular, when associated with significant oedema or malnutrition (homeless, chronic alcohol abuse or return from extreme altitude). Systemic antibiotics are required in the presence of proven infection, trauma or cellulitis (recommendation grade 1C).

Tetanus toxoid

The need for tetanus toxoid administration should be determined by following standard guidelines, as frostbite injuries are not inherently tetanus-prone wounds (recommendation grade 1C).

Analgesia and NSAIDs

Rewarming the extremities can become extremely painful, so use of non-steroidal anti-inflammatory drugs or opiates should be administered. Oral ibuprofen 12 mg/kg divided over two daily doses provides systemic anti-prostaglandin activity that limits the cascade of inflammatory damage. This dose can be increased to a maximum of 2,400 mg/day if the patient is experiencing pain and can be continued until wounds are healed or amputation occurs. A dose of 400 mg BID is a practical regime on which to start most patients, and this can then be increased to 600 mg QDS as pain dictates. If aspirin has not been given in the field (providing no contraindications), 300 mg once a day can be given [4] (recommendation grade 2C).

Iloprost

Iloprost is a prostacyclin analogue with vasodilatory properties that mimic the effects of a sympathectomy [27]. It may also affect platelet aggregation and therefore decrease microvascular occlusion. Unfortunately, intravenous iloprost is not currently available in the USA.

In 1994, Groechenig published his experience in treating four cases of severe frostbite with iloprost [28]. The results were promising, with no patients requiring amputation; however, since these initial findings were published, the focus has shifted towards rTPA, with no further data published on iloprost use until a recent paper by Cauchy et al [29]. In a randomized controlled trial designed to compare the efficacy of iloprost and rTPA, 47 patients were included with a total of 407 digits at risk. All patients underwent identical initial treatment and rewarming and then were randomized into three arms: buflomedil, iloprost or iloprost and IV rTPA. The risk of amputation on the buflomedil arm was the greatest with 39.9% of at-risk digits requiring amputation. In the iloprost and iloprost/rTPA arms, the amputation rates were 0% and 3.1%, respectively [29].

The administration of iloprost is via an IV infusion. The dose used is 0.5 up to a maximum of 2 ng/kg/min [29], incrementally increased every 30 min by 0.5 ng/kg/min until the patient develops unacceptable or intolerable side effects (headache and hypotension). The rate is then reduced by 0.5 ng/kg/min. The infusion is continued for 6 h/day for 5–8 days at the previously determined maximal rate a patient can tolerate.

The advantages of iloprost compared to rTPA are that it does not require radiological intervention during administration and can be managed on a general or vascular ward. Iloprost can be used when there is a history of trauma or when the exposure occurred over 24 h ago, unlike rTPA where trauma is a contraindication and efficacy is reduced beyond 24 h. Figure 3b gives a stepwise approach to iloprost administration (recommendation grade 1B).

FrostBiteExtreme Physiology & Medicine 2014, 3:7

BMJ 2010;341:c5864

Fancy Flourishes At Hospitals Don’t Impress Patients, Study Finds

February 24, 2015 || Kaiser Health News

The sleek hospital tower that Johns Hopkins Medicine built in 2012 has the frills of a luxury hotel, including a meditation garden, 500 works of art, free wi-fi and a library of books, games and audio.

As Dr. Zishan Siddiqui watched patients and some fellow physicians in Baltimore move from their decades-old building into the Sheikh Zayed Tower, the internist saw a rare opportunity to test a widespread assumption in the hospital industry: that patients rate their care more highly when it is given in a nicer place.

For decades, hospital executives across the country have justified expensive renovation and expansion projects by saying they will lead to better patient reviews and recommendations. One study estimated $200 billion might have been spent over a decade on new building. Hopkins’ construction of the tower and a new children’s hospital cost $1.1 billion. Patient judgments have become even more important to hospitals since Medicare started publishing ratings and basing some of its pay on surveys patients fill out after they have left the hospital.

Siddiqui’s study, published this month by the Journal of Hospital Medicine, contradicts the presumption that better facilities translate into better patient reviews. Siddiqui examined how patient satisfaction scores changed when doctors started practicing in the new tower, which has 355 beds and units for neurology, cardiology, radiology, labor and delivery and other specialties.

Siddiqui discovered that for the most part, patients’ assessments of the quality of the clinical care they received did not improve any more than they did for patients treated in the older Hopkins building, which had remained open. Units there were constructed as early as 1913 and as late as 1980, Hopkins officials said. They functioned as the control group in the study, since a hospital’s satisfaction scores often change over time even when a hospital’s physical environment remains constant.

The study used the responses both to Medicare-mandated surveys and private ones from Press Ganey, a consulting company that administers surveys. In the study, Hopkins patient ratings about the cleanliness and quiet in new tower’s rooms — elements Medicare uses in setting pay — soared, as did views on the pleasantness of the décor and comfort of the accommodations. But patient opinions about their actual care — such as the communication skills of doctors, nurses and staff — did not rise any higher than they did in the older building.

“Despite the widespread belief among health care leadership that facility renovation or expansion is a vital strategy for improving patient satisfaction, our study shows that this may not be a dominant factor,” Siddiqui and his fellow authors wrote.

(Photo courtesy of Johns Hopkins Medicine)

The study’s results were startling because previous studies have found that patients in older hospital buildings give lower scores on the quality of their care. Hospital executives have noticed it anecdotally as well; for instance, when NYU Langone Medical Center relocated its cardiology unit to a renovated floor, its patient experience scores rose.

Newer buildings allow for some medical benefits, such as better organized nursing stations and private rooms that protect against the spread of infectious bacteria and diseases. But the Hopkins researchers said “hospitals should not use outdated facilities as an excuse for achievement of suboptimal satisfaction scores.”

A nationwide survey from 2012 conducted by the consultants J.D. Power and Associates reached similar conclusions to the Hopkins paper about the influence of the physical environment on satisfaction scores. That survey found that communication by doctors, nurses and other staff was most important, while the facility accounted for a fifth of patient satisfaction.

After reading the Hopkins study, Dr. Bradley Flansbaum, a physician at Lenox Hill Hospital in Manhattan wrote on the blog of the Society of Hospital Medicine that “it just might be that what doctors do and say matters, and a first-class meal and green gardens cannot paper over, or in the converse, sully our evaluations.”

Kaiser Health News (KHN) is a nonprofit national health policy news service.