**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. In the present review we

**Citation:** Arasi, S.; Mastrorilli, C.; Pecoraro, L.; Giovannini, M.; Mori, F.; Barni, S.; Caminiti, L.; Castagnoli, R.; Liotti, L.; Saretta, F.; et al. Heiner Syndrome and Milk Hypersensitivity: An Updated Overview on the Current Evidence. *Nutrients* **2021**, *13*, 1710. https://doi.org/10.3390/nu13051710

Academic Editor: Yvan Vandenplas

Received: 8 April 2021 Accepted: 17 May 2021 Published: 18 May 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

aimed at presenting clinical, diagnostic and therapeutic characteristics of HS, starting from current evidence. review we aimed at presenting clinical, diagnostic and therapeutic characteristics of HS, starting from current evidence.

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. In the present

### **2. Search Methodology and Results 2. Search Methodology and Results**

*Nutrients* **2021**, *13*, x FOR PEER REVIEW 2 of 14

We carried out a non-systematic review including the most relevant studies on "Heiner Syndrome" (HS) present on databases including PubMed (https://www.ncbi.nlm.nih. gov/pubmed/ accessed on 26 March 2021), MEDLINE, The Cochrane Library, from their inception to 26 March 2021. The searched terms were "Heiner Syndrome" [all fields]; "pulmonary hemosiderosis" and "children" [all fields]; "pulmonary hemosiderosis" and "cow's milk" [all fields]; "pulmonary hemosiderosis" and "hypersensitivity" [all fields]. We found 16 studies. They were all clinical cases or consecutive case series, involving an overall pool of 61 patients. Findings were summarized narratively below for each study as well as in Table 1. We carried out a non-systematic review including the most relevant studies on "Heiner Syndrome" (HS) present on databases including PubMed (https://www.ncbi.nlm.nih.gov/pubmed/ accessed on 26 March 2021), MEDLINE, The Cochrane Library, from their inception to 26 March 2021. The searched terms were "Heiner Syndrome" [all fields]; "pulmonary hemosiderosis" and "children" [all fields]; "pulmonary hemosiderosis" and "cow's milk" [all fields]; "pulmonary hemosiderosis" and "hypersensitivity" [all fields]. We found 16 studies. They were all clinical cases or consecutive case series, involving an overall pool of 61 patients. Findings were summarized narratively below for each study as well as in Table 1.

In order to better stratify the level of evidence for the diagnosis, we are herein proposing the first structured diagnostic criteria for HS to our best knowledge. This diagnostic approach consists of the following criteria: In order to better stratify the level of evidence for the diagnosis, we are herein proposing the first structured diagnostic criteria for HS to our best knowledge. This diagnostic approach consists of the following criteria:


HS diagnosis (HSD): (A) + (B) = probable disease; (A) + (B) + (C) = convincing disease (Figure 1). HS diagnosis (HSD): (A) + (B) = probable disease; (A) + (B) + (C) = convincing disease (Figure 1).

**Figure 1.** Proposed approach for Heiner syndrome diagnosis. **Figure 1.** Proposed approach for Heiner syndrome diagnosis.


**Table 1.** Characteristics of the included studies of Heiner syndrome.

negative; +ve, positive.

Milk precipitins have been evaluated only in some studies, mainly in the oldest ones. Based on current data and specifically due to the heterogeneity in the methodologies applied for laboratory tests, we decided to exclude laboratory parameters from the diagnostic approach.


from the diet, symptomatic therapy and adenoidectomy (when indicated) resulted in improvement in six out of six patients. **Comment:** Even if six out of six patients recovered in 5–21 days after milk removal, only one was rechallenged (Patient C) and one (Patient B) developed pneumonia within six months upon CM reintroduction. **HSD:** Convincing in one case; probable in five patients.


**Comment:** A single patient with HS after a previous history of non-IgE-mediated CM gastrointestinal symptoms. **HSD:** Probable.


after the elimination of milk suggested the diagnosis of HS. In addition to the CM elimination diet, the patient was treated with methylprednisolone (1 mg/kg) and montelukast. **Comment:** Single case report. No milk reintroduction test reported. **HSD:** Probable.
