A 28-Year-Old Man With New Wheezing and an Elevated Blood Count

Answer: D. Cardiac involvement is the most frequent risk factor indication of and cause of mortality.

Discussion. The presented case is that of a young person whose clinical symptoms, new episodes of wheezing, and a background history of “palpable purpura" are suggestive of an allergic/immunologic disorder. When the patient’s routine blood count revealed an elevated eosinophil count, we arrived at the intersection between rheumatology/immunology and hematology: hypereosiophilic syndrome.

Generally, the following numbers are a sound basis for how to interpret eosinophilia. An absolute eosinophil count of 500-1000 on the CBC is common, non-specific as to any etiology and is seen in 3% to 10% of routine blood counts.¹ The next level of note is eosinophils greater than 1500, which is a trigger for an evaluation for underlying cause with high yield for definitive diagnosis. Finally, eosinophil counts above 5000 are entering levels where the number itself presents danger, as these levels are associated with tissue infiltration/damage by eosinophils and their associated proteins causing morbidity regardless of etiology.^1,2

Next to be addressed is the differential diagnosis of an elevated eosinophil count. Detailed tables in the literature generate long lists of potential etiologies.^1,2 The most common pathophysiologic entity is eosinophilia secondary to allergic disorders (e.g. asthma, atopic dermatitis) or drug hypersensitivity. Next, parasites are a usual suspect, but incidence and yield remain very low in the United States. These initial etiologies can rather easily be addressed by history and routine studies. The third pathophysiologic cause is primary blood disorders of the hematopoietic system itself, which has lost its regulatory function and is creating too many eosinophils autonomously. In essence, these are primary blood malignancies-lymphomas, chronic myeloproliferative disorders and other clonal diseases. Their diagnosis and therapeutics fall under eosinophilic granulomatosis with polyangiitis (EGPA), which was formerly known as Churg-Strouss Syndrome.

Generally, EGPA is a syndrome in which for unknown cause there is eosinophilic infiltration of only one target organ: the walls of small and medium sized blood vessels. Indeed, EGPA gives the appearance of multisystem targeting because small- and medium-sized blood vessels are diffuse throughout the body. Unlike the clonal hypereosinophilias, where there are specific genetic markers in the tyrosine kinase and JAK pathways,^3,4 there is no specific blood or genetic test for EGPA. Therefore, as with so many rheumatologic disorders, clinical groups have been developed as a schema for clinical diagnosis. A consensus group definition is "an eosinophil rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis effecting small to medium size vessels associated with asthma and eosinophilia".⁵ The presented patient has enough of the required criteria to make EGPA the presumptive diagnosis. In fact, the presented patient has many of the clinical criteria of the vasculitis phenotype of EGPA, including definitive vasculitis features of biopsy proven necrotizing vasculitis of any organ (the skin biopsy), palpable purpura, hematuria, leukocytoclastic capillaritis, and the presence of anti-neutrophilic cytoplasmic antibodies (ANCA), which is a strong positive lab indication for EPGA but is present in only about half of the patient population clinically diagnosed as EGPA. It is not a requirement for diagnosis.^5,6 Therefore, answer C is an overstatement and is incorrect. To complete the discussion of differential diagnosis of HES, a full 50% of patients with eosinophil counts above 1500 will not have a definitive diagnosis even after full evaluation,¹ which is why the eosinophil count as a number is itself a trigger for therapeutics in situations where hypereosiophilic syndrome is indicated.

Therapeutics are aimed at two areas. When there is a demonstrable etiology causing the increased eosinophils, specific therapies will reverse the eosinophilia. A treatment approach as simple as stopping an offending drug allergen or treating a parasitic infection will resolve the issue. Another interesting subgroup is the clonal myeloproliferative with tyrosine kinase gene rearrangements. These are treated with tyrosine kinase inhibitors.

With the EGPA syndrome, as well as "idiopathic" hypereosiophilic syndrome, the goal of therapy is to lower the eosinophil count toward normal. A key level is less than 5000 absolute eosinophils/mcL since tissue infiltration is unusual below that level. Regardless of eosinophil count, if tissue infiltration has been documented by biopsy therapy is also indicated. Usual target organs requiring protection are kidney and heart.

Cardiac involvement can eventuate in cardiomyopathy and congestive heart failure and is the major mortality cause in EGPA.⁷ This fact makes Answer D correct and Answer B incorrect. Renal infiltration with proteinuria and glomerulonephritis is another significant morbidity as well. The cornerstone of therapy for EGPA is steroids. A variety of initial regimens have been used but two main varieties, depending on the numbers and morbidity facing the physician, are simple prednisone 1 mg/kg for a month with a 4-week taper or, for higher risk situations (high eosinophil count or tissue invasion) pulses of IV methylprednisolone followed by a course of oral prednisone. Response rates exceed 90% but relapse is quite common. Relapse is usually addressed by the addition of a cytoxan regimen followed by maintenance with methotrexate, immuran, or cyclosporin.^5,6 Details and oversight of such treatment are best left to specialists in rheumatology. The role of the primary and generalist physician is to recognize the presence of HES early, as well as the clinical clues accompanying it so as to initiate the evaluation, and then refer appropriately. The current prognosis is quite favorable compared with previous mortality statistics, with 90% 5-year survivorship.⁷ It seems clear that early recognition, diagnosis, and treatment are responsible for this.

What’s The Take Home? Eosinophilic granulomatosis with polyangiitis, also known as Churg-Strauss Syndrome, is a hypereosinophilic syndrome, which is where rheumatology/immunology and hematology meet. Of course, on the way to diagnosis, the usual suspects of allergy, drugs, and parasites need be excluded. But when that has been done, especially in the presence of sustained eosinophil counts above 1500, then a hypereosinphiic syndrome evaluation is indicated. Entities such as EGPA are in the differential, and if certain clinical criteria are present, the diagnosis can be made. As is common in rheumatology, the counting of clinical characteristics comprise of schemas for diagnosis. Fully blown evolved case will feature the "five criteria" described above as well as demonstrating tissue infiltration by eosinophils at any eosinophil count. Biopsy is not required for diagnosis and therapy.

Target organs in addition to skin vasculitis include kidney, heart, lungs, upper airway, and peripheral nerves. In essence, it is the vascular epithelium that is the actual target of the abnormal T lymphocytes and eosinophils, but the syndrome seems multiorgan throughout the body. Therapy is effective especially when initiated early in the disease process. A variety of steroid regimens are effective with cytotoxic agents used in steroid refractory cases. Currently, the overall prognosis is good and much improved from decades past with 5-year survival of 90%. Cardiac involvement is the feared prognostic and responsible for most mortality.

Patient Follow-Up. With the background history of "urticarial rash" going back about 18 months, there was somewhat of a degree of urgency regarding the evaluation and initiation of therapy.  A computed tomography of the chest reveled several small areas of ground glass type infiltrates. Importantly, an echocardiogram was entirely within normal ranges anatomically and functionally. A 24-hour urine collection revealed 1.1 gms protein/24 hr. Cardiac troponins were normal as was creatine phosphokinase level. Ig E was normal. The routine evaluation for parasites was negative, as were JAK-2 studies. A full genetic analysis is pending. ANCA was significantly positive at 1:320. Two more eosinophil counts were in the 6000 range. Prednisone, 1 mg/kg, was initiated and within 10 days the eosinophil count was 890. There have been no episodes of wheezing or rash. The patient will be actively followed regarding his steroid regimen, attempts at weaning, and potential need for further cytotoxic therapy. He currently feels well.

AFFILIATIONS
¹Lewis Katz School of Medicine at Temple University, Philadelphia, PA
²Department of Medicine, Temple University Hospital, Philadelphia, PA

CITATION
Rubin RN. A 28-Year-Old Man With New Wheezing and an Elevated Blood Count. Consultant. 2023;64(1):e5. doi:10.25270/con.2024.01.000002.

DISCLOSURES
The author reports no relevant financial relationships.

CORRESPONDENCE:
Ronald N. Rubin, MD, Temple University Hospital, 3401 N Broad Street, Philadelphia, PA 19140 (blooddocrnr@yahoo.com)

References

1. Klion AD. How I treat hyper eosinophilic syndromes. Blood. 2015;126:1069-1077
2. Meijia R and Nutman TB. Evaluation and differential diagnosis of marked, persistent eosinophilia. Semin Hemat. 2012;49:149-159
3. Gleich GJ, Leiferman KM, Pardanani A, Tefferi A, Butterfield JH. Treatment of hyper eosinophilic syndrome with imatinib mesylate. Lancet. 2002;359:1577-1578
4. Klion AD, Noel P, Aldin C et al Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophia associated with tissue fibrosis, poor prognosis and imatinib responsiveness. Blood. 2003;101:4660-4666
5. Klion AD. How I treat eosinophilic syndromes. Blood. 2015:126:1069-1077
6. Watanabe Ryu and Hashimoto M. Eosinophilic granulomatosis with polyangiitis: latest finding and updated treatment recommendations. J Clin Med. 2023;12:5996-6007
7. Indici M, Pagheux C, Corvosier D, Cohen P et al. Granulomatosis with polyangiitis: study of 795 patients from the French Vasculitis Study Group. Semin Arthritis and Rheum. 2021;51:339-346.

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