Mitigating Disparity in Health-care Resources Between Countries for Management of Hereditary Angioedema

All of the previously published HAE guidelines recommend that diagnosis of HAE with C1-INH deficiency (C1-INH-HAE) should be made by measuring C4, antigenic and functional C1-INH. Genetic diagnosis is not routinely required except in cases trying to differentiate de novo C1-INH mutations from acquired angioedema. The guidelines also recommend that all at risk relatives also be screened [4, 5].

The worldwide prevalence of HAE has been estimated to be approximately 1:50,000 [11]. However, there very little to no epidemiologic data from India and other less developed countries. Considering that the current population of India is approximately 1.38 billion, it is likely that 27,000 patients with HAE exist in the country. However, to the best of our knowledge, there are presently less than 200 diagnosed HAE patients in India. This suggests that 97.26% of patients with HAE remain undiagnosed. A similar situation is likely existing in other low-income countries in Africa and Southeast Asia. Thus, India illustrates the unfortunate and disparate situation seen for HAE patients in many low-income countries compared with higher-income countries. It has been reported that delays in diagnosis of HAE are very common in India, with a median delay in diagnosis of 6.5 years (range 0–28 years) [9]. Of note, it is very typical for parents or grandparents not to receive their initial diagnosis of HAE until their children or grandchildren begin to have symptoms [9]. There are several reasons for these shortfalls:

Our experience with SERPING1 gene sequencing in patients with type 1 HAE at PGIMER in Chandigarh (India) has shown 9 novel (likely pathogenic) and 2 previously reported disease-causing variants in 11 families where a SERPING1 variant could be detected. No disease-causing variants in SERPING1 gene were detected in 9 other suspected families tested [9]. Thus, in our practice, genetic diagnosis failed to diagnose 9/20 (diagnostic sensitivity of 45%) of those with biochemically proven quantitative C1-INH deficiency, while incautious interpretation of variants of unknown significance might risk false positives, reducing specificity of the test. This finding indicates the need to improve access to functional C1-INH assays and differentiate HAE from acquired angioedema which is caused by an anti-C1-INH antibody or an underlying paraproteinemia. Recently, real-time very stable dried blood-spot assays have been developed for functional C1-INH that may address the need for a reliable functional assay in developing countries like India [13]. However, genetic testing may be an effective strategy for diagnosis of family members where the disease-causing gene variant is known and where likely pathogenic variants can be detected. Affordable, genetic testing could overcome otherwise insurmountable challenges in sample transport and thus potentially become a gold standard for definitively diagnosing HAE. Additionally, if C4 and C1-INH are normal in a patient suspected to have HAE, at some centres no further testing is performed and these patients are treated as non-HAE angioedema. Thus, patients with HAE-nl-C1-INH may remain undiagnosed and untreated. In these cases, guidelines emphasize the importance of having heightened clinical suspicion of HAE, based on the presence of angioedema without wheals/urticaria, resistance to regular high dose, second-generation antihistamines and for those with a well-defined family history of angioedema and/or angioedema induced by estrogen. Genetic testing can address the small number of these families with previously defined Factor XII, plasminogen, kininogen and angiopoietin genetic mutations associated with normal complement HAE. However, similar to high-income countries, clinical diagnosis remains essential for the majority of normal complement HAE patients.

Other low-income countries are likely to face similar challenges and, in many countries, there are no immunologists or HAE specialists [HAE International (HAEi), personal communication]. Thus, wider physician recognition of HAE symptoms and clinical characteristics as well as access to pragmatic diagnostic pathways are urgently required in these countries.

We propose Box 1.

Guidelines state that all attacks should be treated with C1-INH, icatibant or ecallantide [4, 5] and should be treated as early as possible, in order to minimize their duration and severity. Upper airway edema should be treated as a medical emergency. All patients should carry an acute attack treatment on their person and be trained on self-administration (with the exception of ecallantide).

The World Allergy Organization (WAO) guideline and emergency department (ED) guidelines [14] emphasizes the need to consider early intubation or tracheotomy in the case of upper airway angioedema [4]. Intubation or tracheotomy is rarely needed where first-line treatments are available but is likely to be of great importance where this is not the case. Guidelines also suggest that plasma may be used if first-line treatments are not available, depending on local availability and safety [4].

Management of HAE in India is a daunting task for patients, families and treating physicians. Most patients have to self-support the cost of therapy for management of most diseases, including HAE. There is no universal health insurance, and only a few patients get financial support from their state or central government.

First-line treatments (C1-INH replacement, ecallantide and icatibant) are not available. These drugs may be imported from other countries and may be used on a compassionate basis for individual patients. However, the cost is prohibitively expensive for almost all patients. Options for acute treatment are limited to fresh frozen plasma (FFP) and attenuated androgens which are often used despite lack of scientific evidence for their efficacy in acute treatment.

FFP contains approximately 1 unit/ml of C1-INH and is a commonly used treatment for acute angioedema attacks in several countries where plasma-derived C1-INH and icatibant are not available. Fresh frozen plasma in a dosage of 10–15 ml/kg has been shown to be effective to abort episodes of acute HAE in some observational studies, but no controlled trials of this treatment exist [15, 16]. Prematta et al. noted success in 22 of 23 patients with attacks at various locations, including laryngeal involvement, in doses of 1–4 units FFP (approximately 250–1000 U C1-INH) [17]. First improvement was noted at 90 min to 12 h, and resolution occurred between 90 min and > 12 h [17]. In another retrospective hospital-based study carried out in Iran and South Africa, FFP treatment was given for 98 of 176 HAE attacks of which 45 attacks involved the upper airway in 43 patients. Attacks were treated with a median (interquartile range: IQR) dose of 400 ml (range 280–560 ml) of FFP, and episodes resolved after a median (IQR) of 4 h (range 2–12 h). Seven patients required a second treatment; 6 were from South Africa, where the initial treatment dose was lower (median 280 ml) compared with Iran (median 560 ml). Of the 45 laryngeal attacks in 43 patients, seven required intubations. Six of these patients were from South Africa, five of whom were intubated before FFP could be given and two because of lack of FFP response. Amongst the 97 potentially life-threatening upper airway attacks, 45 did not receive FFP treatment [18]. Although FFP was found to be effective in aborting most attacks, the response was slow requiring prolonged hospitalization, resulting in increased overall management costs. Furthermore, in Iran and South Africa, 5% patients experienced transfusion reactions including one severe anaphylactic reaction [18]. Another case series from China describes use of FFP (dose 586 ml ± 387 ml) for 16 acute HAE attacks in 13 patients [19]. All but one patient responded with resolution at 3.3 h (range 2–12 h), compared with historical response times of 61.7 ± 27.0 h. Two patients experienced worsening abdominal pain after infusion and one, who did not improve after FFP, experienced a transfusion reaction.

A recent case report from Pakistan described the first HAE treatment with FFP of a man with facial and laryngeal edema necessitating intubation [20]. He was treated with 20 ml/kg with complete resolution after 18 h.

In addition to transfusion reactions, FFP carries other adverse effects of concern, including transmission of pathogens and volume overload. Decades ago, a theoretical risk of aggravation of an acute attack was postulated, as FFP itself contains contact proteins that may lead to excess bradykinin. However, symptom worsening due to FFP has rarely been reported [17]. No data is available on the risk of blood borne pathogens in Iranian, South African or Chinese patients. However, a US retrospective study noted serological evidence of Hepatitis B, C and HIV in 0.97%, 1.93% and 0.19%, respectively in HAE patients treated with FFP [21].

The optimum dose of FFP is unknown. Based on experience with plasma-derived C1-INH, it seems likely that at least 20 ml/kg is required, although, as reported above, lower doses may still prove lifesaving [22, 23].

The requirement to attend a healthcare facility makes it impossible for many patients to be treated promptly to achieve an optimal response. At times, the HAE attack may be severe enough that patients/parents may not even have enough time to reach the hospital for getting an FFP infusion emphasizing the dire need for an acute “on-demand” self-administered therapy in these countries [9].

Tranexamic acid used acutely during an ongoing attack has been reported to potentially prolong the attack [24], but anecdotally some patients have found that very early treatment during a well-defined predictive prodromal period or very shortly after the onset of an attack may be effective at reducing severity [25, 26]. There is, however, very limited trial data to support this observation [27‐30]. Milder attacks (such as peripheral edema and less severe abdominal attacks) may respond to high-dose oral or intravenous tranexamic acid (used in a dose of 1000 mg every 3–4 h for 12–18 h). Likewise, some patients are able to abort attacks by up dosing with attenuated androgens (danazol 200–400 mg or stanozolol 5–7.5 mg) taken immediately upon recognition of prodromal symptoms (e.g. erythema marginatum, severe fatigue or ‘pricking’ sensation) known to result in a subsequent angioedema episode. However, it is widely accepted that androgens are unlikely to contribute to resolution of established attacks.

One of the Indian pharmaceutical companies is currently developing local production of plasma-derived C1-INH, and is awaiting clearance from regulatory authorities. This product is likely to be available on the market by mid-2021. In our experience, completion of the patent period for any particular drug and availability of a locally produced brand leads to drastic fall in the market price of even international Food and Drug Administration (FDA)–approved medications.

We have observed this phenomenon with other analogous high-cost plasma products such as intravenous immunoglobulin (IVIg). At the present time, the cost of locally produced IVIg is at least 3–4 times lower than most international brands, and it is now affordable to patients even for lifelong maintenance treatment. Local production of C1-INH therapy is one of the most effective solutions for patients with HAE in countries like India, as there appears to be no immediate hope of availability and affordability for most other first-line therapies. Given the availability of plentiful C1-INH, a by-product of immunoglobulin and other plasma protein fractionations, we recommend that locally produced C1-INH produced in a formulation and quantity sufficient to provide both acute (intravenous) and prophylactic (subcutaneous) C1-INH replacement at a level expected to provide almost complete freedom from attacks [31]. However, one has to be careful with the safety and efficacy of these plasma-derived products as this is not limited to the actual process of production but also on ‘harvesting’ the raw material and all steps in between. Quality control in this entire process is extremely laborious.

Similarly, now that icatibant, a nonapeptide bradykinin B2 receptor inhibitor, is off patent, there is potential for local production. Although seven generic versions are already available [32‐34], the cost of these treatments would be still prohibitive for most patients with HAE in India and other low-income countries.

Contribution from patient-support societies cannot be overemphasized. In India, several states have now started supporting IVIg treatment for patients with primary immunodeficiency diseases. This has been possible because of consistent efforts from The Indian Society for Primary Immune Deficiency (ISPID): a physician society and two patient organizations (viz. Primary Immunodeficiency Patients’ Welfare Society [PIDPWS] and Indian Patients Society for Primary Immunodeficiency [IPSPI]). A similar patient and physician society for HAE in India (https://​haei.​org/​hae-member-countries/​india/​), affiliated with the HAE International (www.​haei.​org), has recently been established with an aim to increase awareness about this disease amongst physicians and for providing better access to modern treatments.

HAEi is currently working with pharmaceutical companies in a global access program, which has had success in introducing recombinant C1-INH (Ruconest) into many middle-income countries [35]. Oral rapid-acting kallikrein inhibitors are currently in acute trials [36] and may provide more accessible future options.

We propose (Box 2).

Attenuated androgens (danazol, stanozolol, oxandrolone, tibolone) and non-attenuated 17 alpha-alkylated androgens (methyl-testosterone, oxymetholone) are believed to act by increasing intrinsic production of C1-INH.

Double-blind, randomized controlled trials (methyl-testosterone, danazol) and case series (stanozolol, tibolone, oxymetholone, oxandrolone) provide evidence of attenuated androgen effectiveness for LTP in patients with HAE [37]. At high doses, androgens are significantly more effective than placebo in reducing frequency and severity of attacks in more than 90% of patients, including laryngeal attacks [38‐46].

However, the side-effect profile of these drugs, especially at doses higher than the equivalent of danazol 200 mg a day, is a limiting factor for use as long-term prophylaxis. Commonly reported side effects include weight gain, acne, virilization, menstrual irregularities, hirsutism, hepatic abnormalities, growth retardation, behavioural and mood alterations, headache and cardiovascular risk [47]. In our preliminary experience from India, these side effects were common (at variable doses of stanozolol and danazol used) [9]. However, no growth abnormalities in children were observed [9, 48].

In view of these findings, attenuated androgen doses should be adjusted to the lowest possible amount consistent with freedom from attacks. The required dose of stanozolol may range from 0.5 mg taken alternate days to up to 4 mg daily or at doses as high as 8 mg a day for short periods throughout the year. Similarly, the dose of danazol may range from 100 mg alternate days to up to 600 mg per day depending on requirements of individual patients. Some patients may benefit from an ‘alternative prophylaxis’ approach with dose adjustments according to known trigger exposure such as menstruation or infections, or even use of androgens intermittently during high-risk periods only [25, 49].

Anti-fibrinolytic agents (tranexamic acid in a dose of 30–50 mg/kg/day in 2–3 divided doses, maximum dose 3 g/day) are used for LTP, despite paucity of efficacy data [29, 50‐53]. However, better tolerability of anti-fibrinolytic agents compared with attenuated androgens makes them a potential treatment option for LTP especially in children, adolescents and perhaps during pregnancy [37, 51, 54].

There are no studies that have compared the use of attenuated androgens, anti-fibrinolytic agents or a combination of the 2 agents for LTP of HAE. We have used combination of attenuated androgens and tranexamic acid in several of our patients and found no increased risk of thrombosis [9].

Progestins are not specifically mentioned in the guidelines. However, case series suggest that some, although not all, may have modest prophylactic benefits. Specifically, desogestrel (75–150 µg daily), norethisterone (350 µg–10 mg daily) or medroxyprogesterone acetate (150 mg every 3 months; Depo-Provera) may reduce attack frequency. Higher progestin doses and depot preparations are more likely to be beneficial [55]. Oral progestins are safe to use for HAE female patients requiring ongoing or post-coital contraception, as are intrauterine progestin-eluting contraceptive devices. US HAEA Medical Advisory Board 2020 Guidelines have recommended the use of progestins for HAE-nl-C1-INH [56].

The guideline recommendation that all patients should have access to effective treatment for HAE attacks is problematic in resource-poor countries. Despite beneficial experience of attenuated androgens and tranexamic acid as prophylaxis in India, we recently experienced the death of a 16-year-old girl, who, despite receiving dual prophylaxis with stanozolol and tranexamic acid, had a fatal laryngeal edema. She succumbed before her parents could access a hospital FFP transfusion [9]. In addition, at least five patients recall recent deaths of family members because of similar episodes [9]. Education of patients and families to seek help for facial attacks, which may progress to involve the larynx or for laryngeal attacks immediately after onset, when symptoms are typically mild, may minimize mortality, but is no substitute for effective and accessible at home self-administered treatment.

With the advent of orally available small molecule kallikrein inhibitors, there is a desire on behalf of manufacturers to provide the widest possible access. However, the commercial model for such provision is yet to be determined.

We propose Box 3.

In the absence of first-line therapies, FFP is used for acute treatment in a dose of 10 ml/kg and tranexamic acid for STP (at a maximum dose of 15–25 mg/kg twice or three times daily), adjusted for gastrointestinal tolerability and efficacy [63].

Since a greater proportion of children are attack-free compared with adults, the need for LTP is less frequent. Nevertheless, some children are severely affected and if tranexamic acid is insufficient, and first-line therapies are unavailable, attenuated androgens may be unavoidable. While guidelines advise against androgen use prior to Tanner Stage V of puberty, older case reports and series do advocate their use [65, 66]. In view of the potential for adverse effects, the dose should be adjusted to the minimum amount consistent with reasonable freedom from severe attacks and after correction of any underlying precipitating factors. A Hungarian centre describes good tolerability of danazol used as LTP over a period of 2–6 years with a dose of 100 mg every 2–6 days, albeit they did not specify the age group that was treated [26, 65, 66].

Indian experience suggests that while patients experience reductions in attack frequency, adverse effects are common, with virilization and precocious puberty being of particular concern [9, 67]. However, growth retardation appears to be relatively infrequent [9, 48].

We propose Box 5, for children.

Attenuated androgens are potentially teratogenic, with potential to masculinize the female foetus. They may reduce but not completely abolish the ability to conceive and are contraindicated during pregnancy and during breastfeeding. Case reports cite androgen use during pregnancy, without maternal or foetal injury but evidence of safety is lacking [68‐70]. We have reported a case of successful breastfeeding despite danazol use [62], although attenuated androgens may be present in small quantities in breast milk.

Case reports suggest that tranexamic acid may be helpful for HAE during pregnancy but evidence of efficacy and safety, particularly with respect to lack of teratogenicity or thrombosis risk, is lacking. Where C1-INH is not available, tranexamic acid could be considered, preferably after the first trimester [68, 71‐73]. A single case report cites the use of FFP as LTP during pregnancy [74].

We propose that in pregnancy (Box 6).

The WAO guideline recommends that all patients with HAE should be educated about possible triggers, which may induce HAE attacks [4].

Although the trigger is not evident for the majority of HAE attacks, this recommendation is particularly important where recommended acute attack treatments are not available. Angiotensin convertase (ACE) inhibitors and estrogens are known to be major triggers and should be avoided by all patients [28, 75, 76]. Chronic infections such as Helicobacter pylori [77] or inflammatory conditions such as poor dental health [4] or celiac disease [78] or associated immunoregulatory disorders [79] may lower the threshold for swelling. We suggest that these obvious as well as more subtle triggers be proactively identified and treated whenever possible and to encourage preventive medicine including routine dental work.

In addition, it is also important for low-income countries to have an HAE patient organization and to find physicians who are interested and are willing to inform the appropriate healthcare authorities for improving the situation of HAE in the country. This may include reference to other countries with similar income but who have better treatment options for HAE. Contacting HAEi and pharmaceutical companies and using the experience of other countries in a similar situation could be extremely useful.