Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update - XIII - Oral immunotherapy for CMA - Systematic review.

Background: Allergy to cow's milk is the most common food allergy in infants and it is usually outgrown by 5 years of age. In some individuals it persists beyond early childhood. Oral immunotherapy (OIT, oral desensitization, specific oral tolerance induction) has been proposed as a promising therapeutic strategy for persistent IgE-mediated cow's milk allergy. We previously published the systematic review of OIT for cow's milk allergy (CMA) in 2010 as part of the World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. Objective: To systematically synthesize the currently available evidence about OIT for IgE-mediated CMA and to inform the updated 2022 WAO guidelines. Methods: We searched the electronic databases including PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the websites of selected allergy organizations. We included all studies irrespective of the language of the original publication. The last search was conducted in February 2021. We registered the protocol on Open Science Framework (10.17605/OSF.IO/AH2DT). Results: We identified 2147 unique records published between 2010 and 2021, including 13 randomized trials and 109 observational studies addressing cow's milk OIT. We found low-certainty evidence that OIT with unheated cow's milk, compared to elimination diet alone, increased the likelihood of being able to consume ≥150 ml of cow's milk in controlled settings (risk ratio (RR): 12.3, 95% CI: 5.9 to 26.0; risk difference (RD): 25 more per 100, 95% CI 11 to 56) as well as accidently ingest a small amount (≥5 ml) of cow's milk (RR: 8.7, 95% CI: 4.7 to 16.1; RD: 25 more per 100, 95% CI 12 to 50). However, 2-8 weeks after discontinuation of a successful OIT, tolerance of cow's milk persisted in only 36% (range: 20%-91%) of patients. OIT increased the frequency of anaphylaxis (rate ratio: 60.0, 95% CI 15 to 244; rate difference 5 more anaphylactic reactions per 1 person per year, 95% CI: 4 to 6; moderate evidence) and the frequency of epinephrine use (rate ratio: 35.2, 95% CI: 9 to 136.5; rate difference 268 more events per 100 person-years, 95% CI: 203 to 333; high certainty). OIT also increased the risk of gastrointestinal symptoms (RR 6.9, 95% CI 1.6-30.9; RD 28 more per 100, CI 3 to 100) and respiratory symptoms (RR 49.0, 95% CI 3.12-770.6; RD 77 more per 100, CI 62 to 92), compared with avoidance diet alone. Single-arm observational studies showed that on average 6.9% of OIT patients (95% CI: 3.8%-10%) developed eosinophilic esophagitis (very low certainty evidence). We found 1 trial and 2 small case series of OIT with baked milk. Conclusions: Moderate certainty evidence shows that OIT with unheated cow's milk in patients with IgE-mediated CMA is associated with an increased probability of being able to drink milk and, at the same time, an increased risk of serious adverse effects.

Hypersensitivity and adverse reactions to biologics for asthma and allergic diseases.

Introduction: The development of new biologic agents has provided definite therapeutic advances but, like with any new medications, safety remains a concern.Areas covered: Using PubMed, we reviewed the literature on the adverse effects (AE) to five biologics approved for asthma and/or allergic diseases: one anti-IgE (omalizumab), three anti-IL5 (mepolizumab, reslizumab, benralizumab), and one anti-IL4 (dupilumab).Expert opinion: Biologic agents approved for asthma and allergic diseases are generally safe. Most common AE are benign and tolerated, though long-term safety is lacking for most of them. A slightly increased risk of anaphylaxis to omalizumab and reslizumab required the inclusion of a black box warning, informing the patient, the need for post-injection observation period, and the provision of epinephrine autoinjectors for self-administration when needed. Hypersensitivity reactions, mainly urticaria and very rarely serum sickness have occurred.

NAPDH Oxidase-Specific Flow Cytometry Allows for Rapid Genetic Triage and Classification of Novel Variants in Chronic Granulomatous Disease.

PURPOSE: Chronic granulomatous disease (CGD) is an innate immune deficiency, primarily affecting the phagocytic compartment, and presenting with a diverse phenotypic spectrum ranging from severe childhood infections to monogenic inflammatory bowel disease. Dihydrorhodamine (DHR) flow cytometry is the standard diagnostic test for CGD, and correlates with NADPH oxidase activity. While there may be genotype correlation with the DHR flow pattern in some patients, in several others, there is no correlation. In such patients, assessment by flow cytometric evaluation of NADPH oxidase-specific (NOX) proteins provides a convenient and rapid means of genetic triage, though immunoblotting has long been used for this purpose. METHODS AND RESULTS: We describe the clinical utility of the NOX flow cytometry assay through assessment of X-linked and autosomal recessive CGD patients and their first-degree relatives. The assessment of specific NOX proteins was correlated with overall NADPH oxidase function (DHR flow), clinical phenotype and genotype. NOX-specific protein assessment is a valuable adjunct to DHR assessment and genotyping to classify and characterize CGD patients. CONCLUSIONS: The atypical clinical presentation of some CGD patients can make genotype-phenotype correlation with DHR flow data challenging. Genetic testing, while useful for confirmation of diagnosis, can take several weeks, and in some patients does not provide a conclusive answer. However, NADPH-oxidase-specific protein flow assessment offers a rapid alternative to identification of the underlying genetic defect in cellular subsets, and can be utilized as a reflex test to an abnormal DHR flow. Further, it can provide insight into correlation between oxidative burst relative to protein expression in granulocytes and monocytes.

Eosinophilic Esophagitis Clinical Manifestations and Differential Diagnosis.

As a chronic inflammatory disease with eosinophilic infiltrate of the esophagus, eosinophilic esophagitis (EoE) causes a variety of gastrointestinal (GI) clinical manifestations. None of the symptoms, endoscopic features, or biopsy findings is pathognomonic of the disease, even with high degrees of esophageal eosinophilia. The pathogenesis has been explored by several studies, yet it still far from being completely understood. Evidence supports a role of allergen-driven Th2 lymphocyte mechanism, though not in every patient. This article addresses the disease's clinical manifestations, endoscopic findings, diagnosis, and differential diagnoses. In addition to the current diagnostic criteria, we summarize some recently emerging procedures that promise of enhancing more precise diagnosis and institution of early appropriate management, with consequent better quality of life and reduction of complications.

A 24-Year Enzyme Replacement Therapy in an Adenosine-deaminase-Deficient Patient.

Severe combined immunodeficiency (SCID) is a fatal childhood disease unless immune reconstitution is performed early in life, with either hematopoietic stem cell transplantation or gene therapy. One of its subtypes is caused by adenosine deaminase (ADA) enzyme deficiency, which leads to the accumulation of toxic metabolites that impair lymphocyte development and function. With the development of polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) enzyme replacement therapy, many ADA-deficient children with SCID who could not receive a hematopoietic stem cell transplantation or gene therapy survived and had longer and healthier lives. We report a 24-year course of treatment in a patient who was diagnosed with ADA deficiency at 4 months of age. The patient was treated with PEG-ADA, which was the only therapy available for him. The patient's plasma ADA level was regularly monitored and the PEG-ADA dose adjusted accordingly. This treatment has resulted in near-normalization of lymphocyte counts, and his clinical course has been associated with only minor to moderate infections. Thus far, he has had no manifestations of autoimmune or lymphoproliferative disorders. This patient is among the longest to be maintained on PEG-ADA enzyme replacement therapy.

Adverse reactions to infliximab and the outcome of desensitization.

BACKGROUND: Infliximab is a highly effective monoclonal antibody against tumor necrosis factor, which is a major inflammatory mediator in certain gastrointestinal, rheumatic, and skin diseases. In some patients, infliximab infusion causes systemic adverse reactions that often lead to discontinuation of therapy even in responsive patients. OBJECTIVE: To investigate the frequency and characteristics of adverse reactions to infliximab at the authors' institution and the outcome of their management, including desensitization. METHODS: This was a single-center retrospective study of patients who were treated with infliximab, primarily for inflammatory bowel disease, from January 1, 2000 to March 31, 2014. Data included age, sex, underlying disease, infliximab therapy duration before the first reaction, manifestation of reaction, onset, and management. RESULTS: There were 336 patients with inflammatory bowel disease who were treated with infliximab during the study period. Thirty patients (8.9%) developed a systemic adverse reaction to infliximab, which was discontinued in 15 patients (50%) and was continued in 3 patients after premedication and/or decreased infusion rate. Twelve patients (40%) underwent infliximab desensitization with gradually increasing doses starting at a dilution of 0.1 mg/mL to reach the full treatment dose over approximately 4 to 6 hours. It was successful in all 12 patients, who continued to receive up to 26 infliximab infusions, mostly without premedication. CONCLUSION: Infliximab can trigger systemic reactions that hinder its administration. The present desensitization protocol appears to be safe and effective and it can be considered in patients whose inflammatory bowel disease responds well to infliximab but who develop systemic adverse reactions.

Allergy consult for eosinophilia in an infant.

Specialists in allergy/immunology are often asked to evaluate patients with eosinophilia, with the general assumption of an underlying allergic or immunologic disease. We present a case of an infant referred for marked eosinophilia. Although atopic disease may be in the differential diagnosis, it is rarely associated with hypereosinophilia, and other conditions need to be investigated. Until the underlying cause is identified, systemic corticosteroid therapy may be initiated, mainly in severe cases.

Langerhans cell histiocytosis, a case of Letterer Siwe disease.

An 8-month-old male infant presented with a progressively worsening generalized rash of 5-6 months duration, fever, poor feeding, and abdominal distension. An initial laboratory workup revealed anemia, thrombocytopenia, and hepatosplenomegaly. The patient was started on i.v. antibiotics, and a working diagnosis of Langerhans cell histiocytosis was reached that was later confirmed with a skin biopsy. Subsequently, the patient received first-round chemotherapy with vinblastine and prednisone, on which he appeared to improve clinically; however, he soon relapsed. He then received combination salvage therapy with cladribine (2CdA) and cytarabine (Ara-C) for three cycles. The patient responded well to this regimen with resolution of his condition. The patient was then referred for a bone marrow transplant.

Reflections on current food allergy controversies: specific IgE test application, patch testing, eosinophilic esophagitis, and probiotics.

This presentation addresses four selected issues that are current controversies in the area of food allergy. First, the diagnostic proficiency of specific IgE (sIgE) measurement. sIgE testing has been a useful screening test; the higher the level, the more likely to be clinically relevant. However, published predictive values varied from one study to another. Levels derived from data on certain groups of patients reflect probabilities that can not be applied with certainty to individual patients. Several factors need to be considered in interpreting the value of sIgE in any particular patient. Definitive decisions require well-designed challenge testing. Second, a few studies suggested the usefulness of including patch testing in food allergy evaluation. It may reveal positive results that may or may not be clinically relevant. At present, its use is not generally accepted because of inconsistency in the reported findings and the lack of standardization of test materials and interpretation. It may possibly have a role in evaluating eosinophilic esophagitis (EE) more than in atopic dermatitis. Third, EE does not seem to be a new disease or is causing a miniepidemic. Its increasing diagnosis is probably because of a greater awareness and better biopsy assessment. Fourth, the usefulness of probiotics on allergy prevention or treatment has been reported by some studies but not by others. Appropriately designed studies are needed to identify the efficacious type(s) of probiotics, effective doses, method of administration, optimal time to begin, and duration of therapy.

Interleukin-2 treatment for persistent cryptococcal meningitis in a child with idiopathic CD4(+) T lymphocytopenia.

We report a 16-year-old male patient who presented with headache, behavior changes, and fever. His cerebral spinal fluid and blood cultures grew Cryptococcus neoformans. His laboratory evaluation was negative for human immunodeficiency virus infection but flow cytometry revealed low CD4(+) count of 39 cells/mm(3) and CD4:CD8 ratio of 0.43. He was initially treated with antifungal agents with only partial clinical improvement, and he was discharged to home on oral fluconazole and prophylactic co-trimoxazole. After discharge, he continued to have persistent headache and recurrent episodes of vomiting. He was readmitted several times because of worsening of meningitis symptoms and received prolonged courses of multiple antifungal therapy, with clearance of infection from the central nervous system. He was subsequently placed on prophylactic therapy with fluconazole. His peripheral CD4(+) cell count remained low after resolution of his meningitis. Eight months after the initial diagnosis, recombinant IL-2 therapy was initiated and within a few months, his CD4(+) cell count started to increase. Treatment with rIL-2 and prophylactic antifungal therapy continued and he has been asymptomatic for almost 20 months so far. This case is the first reported pediatric idiopathic CD4(+) T-lymphocytopenia case with cryptococcal meningitis that was successfully treated by the addition of rIL-2 therapy to antifungal therapy.

A boy with fever, lymphadenopathy, hepatosplenomegaly, and lymphocytosis.

Proliferation of the lymphoid system should arouse suspicion of a potentially serious illness. We present a 4.5-year-old boy who developed fever, vomiting, diarrhea, lymphadenopathy, hepatosplenomegaly, lymphocytosis, anemia, thrombocytopenia, and increased liver enzymes. Lymph node and bone marrow biopsies showed lymphoproliferation, Epstein-Barr virus (EBV) infection, and hemophagocytosis leading to the diagnosis of hemophagocytic lymphohistiocytosis (HLH). Chemotherapy was initiated for HLH with dexamethasone, etoposide, and cyclosporine. Because of a high level of EBV viremia, rituximab was added a few days later and resulted in a remarkable drop in the EBV in the circulation but not in the cerebrospinal fluid. However, the patient succumbed to encephalitis, pneumonia, and cardiopulmonary failure. Autopsy revealed the presence of EBV in the brain, indicating the ineffectiveness of rituximab therapy in treating central nervous system infection with EBV.

New concepts in the management of adverse drug reactions.

Our understanding of drug reactions and their management has changed markedly in recent years with the development of several new concepts. Epidermal cell death seen in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) may result from Fas-Fas ligand-mediated apoptosis. Intravenous immunoglobulin (IVIG) contains anti-Fas antibodies that can abrogate apoptosis. Most studies on IVIG in SJS and TEN reported improvement in arresting disease progression and reduction in time to healing. Furthermore, several studies have dispelled the myth of sulfonamide cross-reactivity. Immune-mediated reactions against antibacterial sulfonamides are directed against two unique side chains that non-antibacterial sulfonamides do not contain. Certain patients seem to have a genetic predisposition for "multiple drug sensitivities." Hence, they may react to several drugs that are not necessarily cross-reacting. Also, multiple studies have shown that IgE-mediated nonsteroidal anti-inflammatory drugs (NSAIDs) cross-reactivity is uncommon. Rather, it is cyclooxygenase (COX) 1 inhibition that results in pseudoallergic reactions to multiple NSAIDs. Several studies have indicated that selective COX-2 inhibitors can be safely administered in patients with aspirin-exacerbated respiratory disease and NSAID-induced cutaneous reactions, although their use has been curtailed by their cardiovascular side effects. Biological agents, such as infliximab, are being increasingly used for a variety of diseases and have caused adverse reactions in some patients. Studies differ as to whether concomitant immunosuppressive use with infliximab affects the development of drug-specific antibodies and infusion reactions. Successful desensitization protocols have been developed for reactions to some of these agents.

Risk factors for the development of food allergy.

Both genetic and environmental factors seem to predispose to the development of food allergy. A most notable factor is diet, particularly during infancy. Possible other factors include maternal diet during pregnancy and lactation, birth by cesarean section, exposure to tobacco smoke, multivitamin supplementation, and intake of antacids. It is important to identify and control such risk factors to reduce the development of food allergy.

Rhinorrhea not responding to nasal corticosteroids.

A woman with multiple illnesses including allergic rhinitis presented for a follow-up visit at our clinic with constant rhinorrhea for 2 weeks despite regular use of nasal corticosteroids. Two weeks earlier, after alcohol drinking and doubling some of her medications for missed doses, she fell on her face. The Emergency Department records documented headache, bradycardia, hypotension, dehydration, and right infraorbital swelling. She was admitted for hydration and observation, and was discharged after two days without radiologic evaluation of the head. At our clinic, physical examination revealed pale turbinates bilaterally and clear watery discharge from the right nostril. Cerebrospinal fluid (CSF) rhinorrhea was suspected, but glucose testing was not available at our clinic. The patient was immediately admitted into the hospital. A beta-2-transferrin test confirmed CSF from the right nostril. High resolution sinus CT revealed fluid in the right sphenoid sinus, a large cyst in the left maxillary sinus, a cribriform plate dehiscence on the right side, and fluid collection adjacent to the middle turbinate. A lumbar drain was placed to release the pressure and antibiotic prophylaxis was started. Nasal endoscopy revealed CSF leak from the cribriform plate with bone dehiscence and a dural tear. A graft from nasal septal cartilage and temporalis fascia was applied using Tisseal fibrin glue. The persistent rhinorrhea resolved and on follow-up visits, the patient remained asymptomatic. Thinking of CSF rhinorrhea in the differential diagnosis of rhinitis would lead to early diagnosis and prevention of serious medical complications and potential legal liabilities.

Serratia marcescens osteomyelitis in an infant.

Neutrophil dysfunction can result from oxidative burst defect or from glucose-6-phosphate dehydrogenase (G6PD) deficiency; we noted both in the same patient. A 4-month-old male infant with G6PD deficiency presented with swelling of the left middle finger, left leg, and right big toe. At 5 weeks of age he was hospitalized for fever for 2 days. A maternal uncle died at 5 years of age and a male maternal cousin died at the age of 21 months, both reportedly diagnosed with chronic granulomatous disease (CGD). On physical examination, he had a swollen erythematous left third finger, left distal leg swelling, and right big toe abscess. None of these areas was significantly tender. WBC was 18.7 x 10(3)/mm(3) with 37% PMN and 5% bands. The x-ray films showed osteomyelitis in the left third proximal phalanx and the distal right first metatarsal. Culture from the toe abscess grew Serratia marcescens. His neutrophil oxidative burst was tested by the dihydrorhodamine-123 assay and was markedly suppressed, typical of CGD. The mother and maternal grandmother were found to be CGD carriers. He was treated with i.v. antibiotics for 4 weeks and was discharged on prophylactic trimethoprim, itraconazole and interferon gamma, with substantial reduction in infections. Infection in this infant was unusual in its nature, in affecting multiple sites, and in its causative organism. Immune deficiency was suspected, particularly of the phagocytic component, but could not be attributed to his moderate degree of primary G6PD deficiency. Additional immunologic evaluation and the family history led to the diagnosis of X-linked CGD.

Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal necrolysis.

OBJECTIVE: To review the current pathophysiologic mechanisms and recent therapeutic trends in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). DATA SOURCES: A MEDLINE search for SJS and TEN in combination with Fas, Fas ligand (FasL), cytotoxic T cells, intravenous immunoglobulin, and cyclosporine for articles published in English during 1966 to 2006. STUDY SELECTION: Information was derived from original research articles and reviews published in peer-reviewed journals. RESULTS: The hallmark of SJS and TEN is epidermal cell apoptosis, which may be mediated through keratinocyte Fas-FasL interaction or through cytotoxic T-cell release of perforin and granzyme B. Whereas systemic corticosteroid therapy showed contradictory results, intravenous immunoglobulin (IVIG) and cyclosporine have shown promising outcomes. IVIG contains anti-Fas antibodies that can abrogate apoptosis when preincubated with keratinocytes. Most studies on IVIG in SJS and TEN reported improvement in arresting disease progression and reduction in time to skin healing. Because of variations among studies, the findings cannot be optimally compared. In general, mortality varied from 0% to 12% in studies that supported the use of IVIG and 25% to 41.7% in those that did not demonstrate a beneficial effect. Cyclosporine inhibits CD8 activation and thus may reduce epidermal destruction. Relatively few case reports and 1 case series have been published regarding the use of cyclosporine in SJS and TEN. In general, cyclosporine was associated with a significant improvement in time to disease arrest and to complete reepithelization, with no reported fatalities. CONCLUSIONS: Both IVIG and cyclosporine have been associated with enhanced healing and better survival through inhibition of apoptosis. Multicenter, randomized, placebo-controlled trials using a standardized design are needed to validate these findings.

Cerebral lymphoma in an adenosine deaminase-deficient patient with severe combined immunodeficiency receiving polyethylene glycol-conjugated adenosine deaminase.

Polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) provides an alternate therapy to mismatched stem cell transplantation for patients with ADA-deficient severe combined immunodeficiency. Although replacement therapy with PEG-ADA is effective in preventing infections, immune function does not return to normal, and most patients remain lymphopenic. Information is limited regarding the prognosis of patients on long-term ADA-replacement therapy. Here we present a case of a 10-year-old child who was diagnosed with ADA-severe combined immunodeficiency at 4 weeks of age after contracting pneumonia. Treatment with PEG-ADA was begun, the biochemical markers of ADA deficiency normalized, and his clinical progress was very good without significant infections. At 10 years of age, after presenting with headaches and cranial nerve deficits, he was diagnosed with Epstein-Barr virus-positive malignant brain lymphoma. It did not respond to various regimens of aggressive chemotherapy, and the patient expired 5 months later. We speculate that in this patient the immunologic surveillance by T cells may have been defective with respect to elimination of Epstein-Barr virus-infected cells, hence the formation of neoplasm. The possible mechanisms underlying such pathology are reviewed.

Milk-induced pulmonary disease in infants (Heiner syndrome).

Heiner syndrome (HS) is a food hypersensitivity pulmonary disease that affects primarily infants, and is mostly caused by cow's milk (CM). Only a few reports have been published, which may be due to its misdiagnosis. We review here a series of eight cases. When first diagnosed they were 4-29 months of age. They were fed CM from birth and their chronic respiratory symptoms began at age 1-9 months. The symptoms were in the form of cough in seven, wheezing in three, hemoptysis in two, nasal congestion in three, dyspnea in one, recurrent otitis media (OM) in three, recurrent fever in four, anorexia, vomiting, colic or diarrhea in five, hematochezia in one, and failure to thrive (FTT) in two. All had radiologic evidence of pulmonary infiltrates. High titers of precipitating antibodies to CM proteins were demonstrated in six of six and milk-specific immunoglobulin E (IgE) was positive in one of two. Pulmonary hemosiderosis (PH) was confirmed in one patient who showed iron-laden macrophages (ILM) in the bronchoalveolar lavage (BAL), gastric washing, and open lung biopsy. Additional findings, in a descending frequency, were eosinophilia, anemia, and elevated level of total IgM, IgE or IgA. Milk elimination resulted in remarkable improvement in symptoms within days and clearing of the pulmonary infiltrate within weeks. Parents consented to milk challenge in only three cases, all of whom developed recurrence of symptoms. After 2 yr of milk avoidance in one patient, milk challenge was tolerated for 2 months, and then the patient developed symptoms, serum milk precipitins, pulmonary infiltrate, and ILM. The HS should be suspected in young children with chronic pulmonary disease of obscure cause. The diagnosis is supported with a positive milk precipitin test and improvement on a trial of milk elimination. Severe cases may be complicated with PH, which should be suspected in the presence of anemia or hemoptysis and be confirmed with the demonstration of ILM.