Alta J. Terblanche

The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease

Abstract Background: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups (“clinical niches”) have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes. Methods: Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included. Findings: Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches. Conclusions: Several clinical niches have been identified that harbor patients at increased risk of NP-C.

South African food allergy consensus document 2014

The prevalence of food allergy is increasing worldwide and is an important cause of anaphylaxis. There are no local South African food allergy guidelines. This document was devised by the Allergy Society of South Africa (ALLSA), the South African Gastroenterology Society (SAGES) and the Association for Dietetics in South Africa (ADSA). Subjects may have reactions to more than one food, and different types and severity of reactions to different foods may coexist in one individual. A detailed history directed at identifying the type and severity of possible reactions is essential for every food allergen under consideration. Skin-prick tests and specific immunoglobulin E (IgE) (ImmunoCAP) tests prove IgE sensitisation rather than clinical reactivity. The magnitude of sensitisation combined with the history may be sufficient to ascribe causality, but where this is not possible an incremental oral food challenge may be required to assess tolerance or clinical allergy. For milder non-IgE-mediated conditions a diagnostic elimination diet may be followed with food re-introduction at home to assess causality. The primary therapy for food allergy is strict avoidance of the offending food/s, taking into account nutritional status and provision of alternative sources of nutrients. Acute management of severe reactions requires prompt intramuscular administration of adrenaline 0.01 mg/kg and basic resuscitation. Adjunctive therapy includes antihistamines, bronchodilators and corticosteroids. Subjects with food allergy require risk assessment and those at increased risk for future severe reactions require the implementation of risk-reduction strategies, including education of the patient, families and all caregivers (including teachers), the provision of a written emergency action plan, a MedicAlert necklace or bracelet and injectable adrenaline (preferably via auto-injector) where necessary.

Unsuitable blood glucose measuring devices in neonatal or paediatric acute care

A newborn baby with persistent neonatal jaundice developed severe septicaemia. Blood glucose monitoring using Accuchek(R) revealed persistently high values, but laboratory blood glucose testing showed no instance of true hyperglycaemia. She was found to have galactosaemia. The Accu-chek® glucose meter does not discriminate between blood galactose and glucose.

Exclusion diets and challenges in the diagnosis of food allergy

Instituting an exclusion diet for 2 - 6 weeks, and following it up with a planned and intentional re-introduction of the diet, is important for the diagnosis of a food allergy when a cause-and-effect relationship between ingestion of food and symptoms is unclear. Food may be re-introduced after (short-term) exclusion diets for mild-to-moderate non-immunoglobulin E (IgE)-mediated conditions in a safe clinical environment or cautiously at home. However, patients who have had an IgE-mediated immediate reaction to food, a previous severe non-IgE-mediated reaction or a long period of food exclusion should not have a home challenge, but rather a formal incremental food challenge protocol in a controlled setting. An incremental oral food challenge (OFC) test is the gold standard to diagnose clinical food allergy or demonstrate tolerance. It consists of gradual feeding of the suspected food under close observation. It should be done by trained practitioners in centres that have experience in performing the procedure in an appropriate setting. An OFC must be performed in a setting where resuscitation equipment is available in the event of a severe anaphylactic reaction. OFCs are terminated when a reaction becomes apparent. Standardised and pre-set criteria are available on when to discontinue challenges. Patients who tolerate the full dose ‘pass’ the challenge and are advised to eat a full portion of the food at least twice a week to maintain tolerance. Those who have reactions have ‘failed’ the challenge, should avoid the food, receive education and implement risk-reduction strategies where appropriate. Patients should be observed for a minimum of 2 hours following a negative challenge and for 4 hours after a positive one.

Vaccination in food allergic patients

Important potential food allergens in vaccines include egg and gelatin. Rare cases of reactions to yeast, lactose and casein have been reported. It is strongly recommended that when vaccines are being administered resuscitation equipment must be available to manage potential anaphylactic reactions, and that all patients receiving a vaccine are observed for a sufficient period. Children who are allergic to egg may safely receive the measles-mumps-rubella (MMR) vaccine; it may also be given routinely in primary healthcare settings. People with egg allergy may receive influenza vaccination routinely; however, some authorities still perform prior skin- prick testing and give two-stage dosing. The purified chick embryo cell culture rabies vaccine contains egg protein, and therefore the human diploid cell and purified verocell rabies vaccines are preferred in cases of egg allergy. Yellow fever vaccine has the greatest likelihood of containing amounts of egg protein sufficient to cause an allergic reaction in allergic individuals. This vaccine should not be routinely administered in egg allergic patients and referral to an allergy specialist is recommended, as vaccination might be possible after careful evaluation, skin-testing and graded challenge or desensitisation.

South African Food Allergy Working Group (SAFAWG) authors of the South African food allergy consensus document 2014

South African Food Allergy Working Group (SAFAWG) authors of the South African food allergy consensus document 2014

Diagnosis of food allergy: History, examination and in vivo and in vitro tests

One cannot depend on one single test to diagnose food allergy. A detailed history is an essential initial step in cases of suspected food allergy. Aspects of the history should be gathered separately for each food being considered, as a patient may experience different types of reactions with various foods, each of which requires individual diagnostic and management strategies. History alone is not diagnostic and additional measures of sensitisation or food challenges are often required. In suspected immunoglobulin E (IgE)-mediated allergy, skin-prick tests (SPTs) and/or measurement of serum specific IgE antibodies (ImmunoCAP) to suspected foods is used to prove sensitisation. Sensitisation does not, however, confirm clinical food allergy as these tests indicate an immunological response to the specific allergen, but the diagnosis requires a clear correlation between the test result and clinical reaction (by positive history or food challenge). The magnitude of the test result (SPT mean wheal size or ImmunoCAP level in kU/L) correlates with the likelihood of clinical allergy, but not the severity of a reaction. Choice of the allergens tested should be guided by the history, but limited to the lowest necessary number to avoid false-positive results. Tests for sensitisation to foods should not be performed when the history indicates that such foods are tolerated. Ninety-five per cent positive predictive values (where a clinical reaction can be predicted in 95% of cases) have been described for immediate reactions, but may be population specific. There are no validated tests to confirm non-IgE- or mixed IgE- and non-IgE-mediated food allergies. Diagnosis of this group of allergies depends on elimination of the suspected food, clearance of symptoms, and recurrence of symptoms on re-introduction of the food.

Severe food allergy and anaphylaxis : treatment, risk assessment and risk reduction

An anaphylactic reaction may be fatal if not recognised and managed appropriately with rapid treatment. Key steps in the management of anaphylaxis include eliminating additional exposure to the allergen, basic life-support measures and prompt intramuscular administration of adrenaline 0.01 mg/kg (maximum 0.5 mL). Adjunctive measures include nebulised bronchodilators for lower-airway obstruction, nebulised adrenaline for stridor, antihistamines and corticosteroids. Patients with an anaphylactic reaction should be admitted to a medical facility so that possible biphasic reactions may be observed and risk-reduction strategies initiated or reviewed after recovery from the acute episode. Factors associated with increased risk of severe reactions include co-existing asthma (and poor asthma control), previous severe reactions, delayed administration of adrenaline, adolescents and young adults, reaction to trace amounts of foods, use of non-selective β-blockers and patients who live far from medical care. Risk-reduction measures include providing education with regard to food allergy and a written emergency treatment plan on allergen avoidance, early symptom recognition and appropriate emergency treatment. Risk assessment allows stratification with provision of injectable adrenaline (preferably via an auto-injector) if necessary. Patients with ambulatory adrenaline should be provided with written instructions regarding the indications for and method of administration of this drug and trained in its administration. Patients and their caregivers should be instructed about how to avoid foods to which the former are allergic and provided with alternatives. Permission must be given to inform all relevant caregivers of the diagnosis of food allergy. The patient must always wear a MedicAlert necklace or bracelet and be encouraged to join an appropriate patient support organisation.

Should the routine approach to diarrhoea management be modified in an area of high prevalence of paediatric HIV infection

or urinary infection. Patients with diarrhoea were more likely to be tested for HIV if they were severely malnourished or clinically wasted, if they had hyponatraemia or hypokalaemia, and if they had hepatomegaly or lymphadenopathy. The presence of shock or severe dehydration on admission, or of comorbid pneumonia, did not differentiate between those who were tested for HIV and those who were not. There were statistically significant differences between those tested for HIV and those not tested in respect of outcome. Among the children tested for HIV, 24.2% of survivors had a prolonged hospital stay (more than 10 days), compared with 1.4% among those not tested (p<0.005). While more children in the group tested for HIV died in hospital (6.1% v. 2.6%), this did not reach statistical significance (p=0.466). Conclusion. In this study, HIV testing was found to be predominantly based on clinical grounds at the time of admission. Because of considerable clinical overlap between diarrhoea patients with and without HIV infection, HIV co-infection cannot be reliably predicted on clinical features alone and must be actively excluded. Effective ART is now available. All patients with diarrhoea must therefore be offered HIV testing to provide earlier access to appropriate management.

Adjunctive corticosteroid treatment of clinical PCP pneumonia in infants less than 18 months of age: a randomized controlled trial

Objectives. To determine the efficacy and safety of adjunctive corticosteroid therapy in clinical PCP pneumonia (Pneumocystis jiroveci pneumonia) in infants exposed to HIV infection. Design. Double blind randomised placebo-controlled trial. Methods: Infants with a clinical diagnosis of PCP, based on an “atypical” pneumonia with: 1) hypoxia out of proportion to the clinical findings on auscultation, 2) CRP less than 10 IU, 3) LDH above 500 IU, 4) compatible CXR findings and 5) positive HIV ELISA test were included in the study. Patients were randomised to receive either prednisone or placebo. The protocol provided for the addition of prednisone to the treatment at 48 hours if there was clinical deterioration or an independent indication for steroid therapy. Other treatment was carried out in accordance with established guidelines. The primary study endpoint was in hospital survival. Secondary outcome was time from admission to the first day of mean oxygen saturation above 90% in room air. Results. One hundred patients were included, 47 in the prednisone and 53 in the placebo group. Patients in the prednisone group had a 43% better chance of survival than the placebo group (HR 0.57, 95% CI 0.30-1.07, p=0.08). No significant differences could be demonstrated between groups in respect of other parameters of recovery. Conclusions. In HIV exposed infants with clinical PCP pneumonia, adjunctive corticosteroid treatment does not appear to add benefit regarding time to recovery or oxygen independency, but early administration may improve survival. A large multi-centred trial is needed to confirm these findings. Key words: Pneumonia, Pneumocystis jiroveci, PCP, HIV infection, infants, corticosteroid therapy