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    Topic review

    Heiner Syndrome and Milk Hypersensitivity

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    Submitted by: Stefania Arasi

    Definition

    Infants affected by Heiner syndrome (HS) display chronic upper or lower respiratory tract infections, including otitis media or pneumonia. Clinically, gastrointestinal signs and symptoms, anemia, recurrent fever and failure to thrive can be also present. Chest X-rays can show patchy infiltrates miming pneumonia. Clinical manifestations usually disappear after a milk-free diet. The pathogenetic mechanism underlying HS remains unexplained, but the formation of immune complexes and the cell-mediated reaction have been proposed. Patients usually outgrow this hypersensitivity within a few years.

    1. Introduction

    Heiner syndrome (HS) is a rare food-induced hypersensitivity disease characterized by chronic respiratory symptoms with X-ray (XR) infiltrates, and the resolution of signs and symptoms after the removal of milk proteins. Other clinical manifestations include poor growth, gastrointestinal signs and symptoms, iron deficiency anemia and pulmonary hemosiderosis (PH). Precipitins to cow’s milk (CM) were also considered a useful aid in recognizing hypersensitivity to CM [1]. The literature concerning HS is restricted to a few case reports or series, although the disease has always been described at infant or pediatric age [2]. The definition of the disease is lacking and the diagnosis is often delayed, since its presentation is uncommon with dissimilar manifestations.

    2. Age at Onset

    The clinical onset of the disease has been described typically by the age of 1 month to 48 months, but it can develop even during the first 5 days of life, as reported by Torres et al. [3]. However, it can also appear later (the oldest patient was 5 years old) [4]. Nevertheless, there was a frequent delay in diagnosing this disease, due to its various modes of presentation and lack of standardized diagnostic criteria. The past medical history of affected children was always unremarkable. A family history of allergic disorders was often present. Differently from immediate-onset IgE-mediated CM allergy, HS did not display signs and symptoms before several days or weeks after CM consumption.

    3. Etiology

    Although HS is more likely to be induced by homogenized CM, the disease also may occur in some infants fed with CM-derived formula. Furthermore, it has been speculated that it can be related to non-IgE-mediated allergy to food proteins differently from CM at an older age (e.g., soy, egg, pork, wheat and peanut) [5][6]. In this context, a single case of PH hemosiderosis due to buckwheat has also been reported [7].

    4. Clinical Characteristics

    Respiratory features of the disease included persistent cough, dyspnea, tachypnea, wheezing, occasional sputum production and rales. The peculiarity of pneumonia in these case series was the refractoriness of antibiotic treatments. Of note, in most cases, the additional administration of anti-inflammatory drugs probably might have resolved hypersensitivity pneumonia or idiopathic PH (IPH). The most commonly described systemic clinical manifestations were intermittent fever, progressive anorexia and FTT. Inflammatory markers were usually found to be high. Eosinophilia and severe iron deficiency anemia were frequently described at blood count examination. Gastrointestinal manifestations were reported in about half of the patients and included frequent vomiting or diarrhea. Rarely, lymph node hypertrophy with hepatomegaly, splenomegaly and hypertrophied tonsils or adenoids were labeled [8]. Noticeably, lymphonodular hyperplasia in biopsy was found in a child with HS-manifesting hematochezia [9].
    Clinically, the disease can be complicated with cardiopulmonary involvement, such as alveolar hypoventilation, massive acute PH, pulmonary hypertension and cor pulmonale, or nephrological ones, such as crescentic glomerulonephritis [10][11]. These characteristics contributed drastically to morbidity and emerged in situations of overdue diagnosis and management. In particular, a delayed manifestation of the disease is episodic hemoptysis, which may represent a PH with repeated episodes of intra-alveolar bleeding, hemosiderin deposition in alveolar macrophages, followed by the development of pulmonary fibrosis and severe anemia [10]. PH may occur as a primary disease of the lung (also called IPH) or secondary to cardiac diseases, bleeding disorders, collagen-vascular diseases or systemic vasculitis. IPH, if not treated, leads to progressive pulmonary fibrosis and may be lethal [12].

    5. Pathogenesis and Immunological Implications

    The exact mechanism that triggers HS is not fully understood. Feasibly, the formation of immune complexes is strongly suspected (Gell and Coombs type III reaction) and the cell-mediated reaction (Gell and Coombs type IV reaction) may contribute to the development of this challenging disease.
    Some cases showed positive skin tests [13][8], high serum total IgE levels [8], high milk-specific IgE antibodies [11][5] or circulating immune complexes [13]. A significant increase of histamine and ECP in BAL several hours after a milk OFC was reported [3]. In one case report, deposits of immunoglobulins, complement, fibrin and milk protein antigens diffusely scattered were described on immunofluorescence studies of lung tissue biopsies [2]. It is probable that a cause concurring to HS is the aspiration of milk, in particular among patients with an uncoordinated swallowing mechanism, tracheal/esophageal anomaly or gastroesophageal reflux. However, in the paper of Boat et al., this condition was ruled out [8]. Concerning the data on delayed immunity, in some cases a delayed skin test response to intradermal test [13][8] or a lymphocyte response [10] was reported. Other authors postulated that milk antigens might trigger an immune complex reaction resulting in multiorgan abnormalities, such as pulmonary, gastrointestinal and renal ones. In fact, pulmonary and gastrointestinal signs and symptoms were frequently associated [14] and granular immuno-deposits have been demonstrated along the glomerular basement membrane in a child with crescentic glomerulonephritis and PH [11].
    Most studies, mainly the oldest ones, characteristically found high titers of precipitins (likely immunoglobulins of class G) against bovine milk proteins in the patients’ sera, by using the Ouchterlony double-immunodiffusion technique [4][15][8][14]. However, it is not sufficiently explicable why some children develop precipitating antibodies to ingested protein and other children do not. Moreover, it is not known if these precipitins play a causative role in the disease. Children with precipitins usually have an increased incidence of recurrent respiratory tract diseases, anemia and hepatosplenomegalia. However, precipitating IgG antibodies to milk are not pathognomonic of the disease, since they have been found among around 1% of healthy children in the absence of clinical manifestations [4], and in 4% to 6% of children with chronic disorders, including celiac disease, cystic fibrosis, IgA deficiency, Down’s syndrome, Wisckott–Aldrich syndrome and Hurler’s syndrome [8]. Additionally, methods used for detecting precipitins are obsolete and reports on them are timeworn. Therefore, the role of these antibodies should be critically considered.
    In other more recent reports, high values of specific IgG to milk proteins were found using an immunoenzimatic technique [5]. In one case report [16] CM IgG4 was found to be elevated. Even in these cases, the role of this specific CM IgG is not clear.

    6. Pulmonary Modifications and Immunofluorescence Studies

    Chest roentgenograms displayed variable patchy and transient infiltrates, frequently associated with areas of atelectasis, consolidation, reticular opacities, pleural thickening or hilar lymphadenopathy. The lung biopsy obtained in patients who had hemoptysis showed an abnormal accumulation of hemosiderin in the lungs, which resulted in alveolar hemorrhage or PH [2]. Among patients with anemia and hemoptysis, PH was verified by the demonstration of iron-laden macrophages by using Prussian Blue staining of bronchial aspirates or morning gastric washes [10].

    7. Diagnostic Criteria

    As described in detail above, in order to better stratify the level of evidence for the diagnosis, we are herein proposing the first structured diagnostic approach for the diagnosis of HS to the best of our knowledge. We auspicate that this approach may allow clinicians to stratify patients with a clinical history consistent with the suspicion of HS in probable (criteria A + B) or convincing (criteria A + B + C) HS (Figure 1). According to our criteria, only 6 out of 61 patients had a convincing clinical diagnosis of HS, in 25 patients the clinical diagnosis was probable and in the others the HS diagnosis was doubtful (Table 1). Due to the heterogeneity in the methodologies applied for laboratory tests and missing reporting/lack of data, we decided to exclude laboratory parameters from the diagnostic criteria. We suggest in the future that milk-specific IgG tests with current diagnostic methods (i.e., immunoenzymatic), in the case of suspected HS, could be studied. Nevertheless, further points remain questionable in our proposed diagnostic approach. First, some cases of occurrence of signs and symptoms during exclusive maternal breastfeeding were reported (e.g., in three out of seven cases in Heiner et al. [13], leading to the question of whether or not minimal quantities of CM passing in breast milk are capable of inducing a clinical response through an IgG-mediated mechanism in the infant). As a second observation, one case of resolution of signs and symptoms without dietary restriction has been described (one out of seven patients from Heiner et al.). Again, a real, controlled OFC of milk was reported only in 6 cases [13][8][14] and a recurrence of clinical manifestations was reported in a further 6 cases (although without details on exact timing of the symptoms’ onset) based only on clinical history [15][17][8][11][5][18], for a total of 12 cases. Moreover, in some cases [11][5] pharmacological therapy was associated to the CM elimination diet, making it difficult to differentiate the effect of each single treatment. Spontaneous resolution of signs and symptoms also occurred in some cases of HS [1]. Furthermore, some studies did not report on the follow-up and specifically on the outcome of any CM reintroduction. In conclusion, even if in a few cases a convincing diagnosis can be made using specific criteria, certainty is lacking due to the incomplete clinical and imaging monitoring of the OFC and the lack of control cases.
    Figure 1. Proposed approach for Heiner syndrome diagnosis.
    Table 1. Characteristics of the included studies of Heiner syndrome.
      Authors, Year Country n. Cases Age at Onset (Months) Signs/Symptoms Lung
    Radiologic Infiltrates
    Pulmonary
    Hemosiderosis
    Hemosiderosis Diagnosis Milk
    Precipitins
    Delayed Hypersensitivity Allergic
    Sensitization to Milk [sIgE and/or skin prick test (SPT)]
    Improvement Upon Milk Avoidance Recurrence Upon Milk
    Reintroduction
    1 Heiner, 1960 USA 7 1–17 chronic cough (7/7); wheezing (7/7); chronic rhinitis (7/7); frequent fever (7/7); frequent earache (6/7);
    diarrhea (6/7); vomiting (5/7); hemoptysis (4/7)
    yes,
    recurrent
    yes (5/7) gastric or bronchial aspirates (4/7); pulmonary needle biopsy (1/7) yes intradermal test (ID) late response pos (4/7) ID +ve (7/7) yes (6/6) yes (2/6)
    2 Holland, 1962 USA 22 4–12 respiratory disease; failure to thrive (FTT); anemia; splenomegaly;
    hepatomegaly
    non specified (NS) NS NS yes NS NS yes (22/24 on milk-free diet) NS
    3 Chang, 1969 USA 1 9 FTT ;
    anemia; chronic recurrent lung disease
    yes NS NS yes NS NS yes doubtful, based on clinical history (CH)
    4 Archer, 1971 England 1 13 iron-deficiency anemia; lethargy; pallor; bloody vomit; severe cardiac
    failure; hemoptysis
    yes yes needle biopsy no NS SPT –ve yes doubtful, based on CH
    5 Boat, 1975 USA 6 7–48 idiopathic chronic or recurrent pulmonary disease; upper respiratory symptoms; FTT (3/6); frequent regurgitation and watery stools (1/6). SOF (1/6): Iron deficiency (5/6); Anemia (4/6); Eosinophilia (4/6); right ventricular hypertrophy (3/6); adenoid hypertrophy (3/6) yes (6/6) yes (5/6) gastric
    washing or bronchoalveolar lavage (BAL)
    yes (6/6) 4 ID delayed
    response
    total IgE –ve (6/6); SPT +ve (5/6) yes (5/6); 1/6 loss of data yes (1/6)
    6 Stafford, 1977 USA 7 8–48 wheezing (5/9); chronic rhinitis (3/9); large adenoids/tonsils (4/9); anemia (4/9); gastrointestinal symptoms (4/9); eosinophilia (6/9) yes (7/9) yes (3/9) gastric washing and BAL yes (9/9) lymphocyte
    response (3/3)
    SPT +ve (6/9), sIgE +ve (5/8) NS NS
    7 Fossati, 1992 Italy 1 7 years anemia; respiratory symptoms yes yes NS yes NS NS yes NS
    8 Torres, 1996 Spain 1 0 (5 days) vomiting with blood; respiratory failure; restrictive miocardiopathy; anemia; eosinophilia yes (chest X-Ray, CXR) yes BAL NS NS neg yes symptoms not reported
    9 Moissidis, 2005 USA 8 4–29 cough (7/9); wheezing (3/9); dyspnea (1/9); hemoptysis (2/9); nasal congestion (3/9); recurrent otitis media (OM) (3/9); recurrent fever (4/9); gastrointestinal symptoms (5/9); in 7/8; hematochezia (1/9); FTT (2/9); eosinophilia in 5/8 yes (9/9) yes (1/9) NS yes (6/6) NS sIgE (1/3), SPT (1/2) yes (8/9) positive challenge (3/3)
    10 Sigua, 2013 USA 1 12 persistent cough; progressive anorexia; intermittent fever; weight loss; iron deficiency anemia yes (CXR) no BAL yes NS sIgE –ve yes doubtful, based on CH
    11 Yavuz, 2014 Turkey 1 36 respiratory distress; hemoptysis; recurrent bronchitis; FTT; iron deficiency anemia; eosinophilia; increased inflammatory index; yes (CXR, CT) yes BAL NS NS sIgE +ve yes doubtful, based on CH
    12 Mourad, 2015 USA 1 17 severe anemia; respiratory distress yes (CXR) yes BAL IgG NS sIgE +ve yes doubtful, based on CH
    13 Alsukhon, 2017 USA 1 2 FTT; recurrent diarrhea; persistent cough; tachypnea; high inflammatory markers yes (CXR) NS NS IgG4 NS sIgE –ve yes NS
    14 Ojuawo, 2019 Nigeria 1 4 FTT; cough; dyspnea; wheeze; rhinitis; gastrointestinal symptoms; anemia yes (CXR) NS NS NS NS NS yes NS doubtful, based on CH
    15 Koc, 2019 Turkey 1 6 massive hemoptysis; hematemesis; deep anemia yes (CXR, CT) yes gastric washing NS NS NS yes NS
    16 Liu, 2020 China 1 4 respiratory failure; hematochezia; diarrhea; elevated WBC and C-reactive protein yes (CXR, CT) no sputum or fasting gastric fluid NS NS –ve yes NS
    Abbreviations: BAL, bronchoalveolar lavage; CH, clinical history; CT, computerized tomography; CXR, chest X-Ray; ID, intradermal test; NS, non specified; SPT, skin prick test; –ve, negative; +ve, positive.

    8. Differential Diagnosis

    In the differential diagnosis (DD) bronchial asthma, chronic aspiration, acute and chronic lower respiratory tract infections, including fungal ones, cystic fibrosis, foreign body, hypersensitivity pneumonitis, bronchopulmonary aspergillosis, secondary PH and IPH should be considered [14]. Cystic fibrosis essentially can be excluded by a normal chloride level on the sweat test and second line tests if there is a strong suspicion. Infectious causes should be ruled out with tuberculin skin test and available microbial tests, and empiric antibiotic treatments characteristically are inefficacious. Thereafter, a vasculitis or autoimmune disorder can be considered. The characteristic pulmonary hemorrhage attacks cannot be enlightened by modest bronchial asthma. The lack of chronic inhalant exposure and BAL examination can rule out hypersensitivity pneumonitis. Bronchopulmonary aspergillosis is unlikely if skin reactivity to Aspergillus antigens is negative or precipitating serum antibodies to A. fumigatus are absent. No hemorrhagic focus nor foreign bodies can be found on bronchoscopy. In particular, DD should consider IPH, that includes the classic triad hemoptysis, radiologic lung infiltrate and iron deficiency anemia, having a more severe course and prognosis [19]. Moreover, IPH occurs in older children, and it is rarely associated with gastrointestinal symptoms [20] (Table 2).
    Table 2. Differential diagnosis between Heiner syndrome (HS) and idiopathic pulmonary hemosiderosis (IPH).
      HS IPH
    Age infants or young children older children/adults
    Hemosiderosis often always
    GI symptoms often rarely
    Precipitins yes no
    Response to diet yes no
    Prognosis good variable

    9. Natural History

    The disease’s effects were reversible by stopping CM consumption. In fact, signs and symptoms could last within a time range of 5 to 21 days after the CM withdrawal. Before CM reintroduction, some children showed spontaneous tolerance to pasteurized or boiled CM [4]. Reoccurrence of clinical manifestations was reported with CM reintroduction [13][15][17][3][14][5]. However, it is believed that patients usually definitively outgrow this hypersensitivity, and they can tolerate CM within a few years [14][21][22].

    10. Treatment

    Clinical improvement with strict elimination of CM proteins sustains the diagnosis of HS. Infants may be fed by a milk substitute, such as extensively hydrolyzed protein formula, soy-based formula or synthesized free amino acid formula. Improvement of signs and symptoms occurs in few days and X-ray images in weeks. When a confirmatory CM reintroduction was performed [14], respiratory clinical manifestations also occurred in days or weeks. An early exclusion of the triggering food from the diet is crucial, since chronic PH induces pulmonary fibrosis which can be fatal [17]. However, recovery may occur also without exclusion of the culprit food (e.g., 1/7 in Heiner’s report [13]).
    Even if the most striking criterion of HS is the dramatic response to the exclusion diet, initially, in some cases, appropriate treatment, e.g., bronchodilators, antihistamines, systemic or inhaled steroids and iron, may be needed. A short cycle of oral corticosteroids remains the first-line therapy for acute attacks. In more severe cases of HS, other immunomodulatory treatments may be helpful, such as hydroxychloroquine, azathioprine or cyclophosphamide. On the contrary, antibiotic therapy seems not to be useful.

    This entry is adapted from 10.3390/nu13051710

    References

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    2. Lee, S.K.; Kniker, W.T.; Cook, C.D.; Heiner, D.C. Cow’s milk-induced pulmonary disease in children. Adv. Pediatr. 1978, 25, 39–57.
    3. Torres, M.J.; Girón, M.D.; Corzo, J.L.; Rodriguez, F.; Moreno, F.; Perez, E.; Blanca, M.; Martinez-Valverde, A. Release of in-flammatory mediators after cow’s milk intake in a newborn with idiopathic pulmonary hemosiderosis. J. Allergy Clin. Immunol. 1996, 98, 1120–1123.
    4. Holland, N.H.; Hong, R.; Davis, N.C.; West, C.D. Significance of precipitating antibodies to milk proteins in the serum of infants and children. J. Pediatr. 1962, 61, 181–195.
    5. Mourad, A.A.; Parekh, H.; Bahna, S.L. A 17-month-old patient with severe anemia and respiratory distress. Allergy Asthma Proc. 2015, 36, 506–511.
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    8. Boat, T.F.; Polmar, S.H.; Whitman, V.; Kleinerman, J.I.; Stern, R.C.; Doeshuk, C.F. Hyperactivity to cow milk in young children with pulmonary hemosiderosis and cor pulmonale secondary to nasopharyngeal obstruction. J. Pediatr. 1975, 87, 23–29.
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