A 20-Year-Old Man With A Severe Sore Throat And Fatigue

ANSWER: C. Obtain a bone marrow biopsy

Discussion. The young man showed a somewhat acute presentation of profound pancytopenia now manifesting several complications related to his lowered counts, namely fatigue from anemia, bleeding manifestations from a severe thrombocytopenia, and a necrotic pharyngitis related to his neutropenia. The absence of a preceding illness or other organ symptomatology very quickly focuses our attention to a serious primary blood disorder. We can quickly dispense with answers A and B. The patient manifests not only anemia and thrombocytopenia but also neutropenia, profound at that, all of which point to bone marrow failure rather than peripheral destruction seen with autoimmune hemolysis and immune thrombocytopenic purpura. Further, the bilirubin is normal, and we might expect some elevation with an autoimmune hemolyis. Epstein-Barr mononucleosis is common in his age group and can cause a necrotic sore throat. His age and social setting are right for mononucleosis as well. However, mononucleosis does not cause a severe pancytopenia as seen here except in the rarest of instances. One would also expect to find splenomegaly and some lymphadenopathy as well. The evidence on presentation suggests a bone marrow failure syndrome and the way to quickly confirm that diagnosis is to perform a bone marrow biopsy making Answer C the correct choice.

In aplastic anemia, which was the diagnosis here, there is loss of hematopoietic stem cells of all the formed element cell lines: red blood cell count (anemia), polymorphonuclear WBC (neutropenia), and megakaryocytes (thrombocytopenia). Thus, the marrow becomes "empty", which is shown by a bone marrow biopsy revealing only fat and scattering of lymphcytes and plasma cells rather than the 50% normal cellularity composed of all the morphologically divergent forms of the normal precursors. The disease is rare, but formally deadly, with nearly 100% mortality. Fortunately, this has remarkably improved in recent decades.

What are the potential causes of stem cell depletion of the marrow? Three basic pathophysiologies have been described. One is genetic disorders, the most well-described of which is the spectrum of Fanconi's syndrome in which defects in DNA repair in the hematopoietic stem cells are causal.^1,2 Such cases are mainly seen in pediatric populations and account for a minority (5%) of aplastic anemia cases.²

Direct toxic effects on the marrow by radiation and/or chemotherapeutic agents cause cytopenia. Generally, there is significant recovery with time although milder cytopenias can remain due to permanent damage to the hematopoietic stem cells due to the radiomimetic properties of these drugs. These entities will have an obvious history of exposures in patients with cytopenias related to these agents.

The most common causation in adults with aplastic anemia (70% of cases) is idiopathic autoimmune destruction of stem cells. A precise concept of mechanism has been developed and involves the autoimmune activation of cytotoxic T lymphocytes producing cytokines that induce apoptosis of hematopoietic stem cells and precursors.² The diagnosis of the idiopathic form of aplastic anemia is given to patients with pancytopenia, an "empty marrow" in an adult patient without Fanconi's syndrome (e.g. excessive warts, thumb and facial deformities, family history and age of onset in childhood) or history of exposure to marrow radiation or toxins. As previously stated, profound pancytopenia is a firm indication for bone marrow biopsy, which also serves to exclude other marrow diseases such as acute leukemia. The latter almost always will manifest abnormal forms like blasts and other early precursor cells, which makes Answer D less likely and incorrect. But the bone marrow biopsy would be definitive. Further, our patient does not have adequate numbers of peripheral blood cells for a reliable flow cytometry study.

Therapeutics for aplastic anemia have been revolutionized by advances in immunology made in both hematopoietic stem cell transplantation and immunosuppression.^1,3 In addition, these developments have diffused into oncology, solid organ transplantation, and other fields. For aplastic anemia, hematopoietic stem cell transplantation, or bone marrow transplant (BMT) is curative when successful and at least for now is the preferred treatment if possible.^{1, 2}. A properly matched human leukocyte antigen-compatible donor is required to avoid difficult and even deadly complications of graft versus host disease. This is best provided by sibling donors but donor registries in the general population are now becoming common. In a "young" patient, defined in BMT terms as less than 40 years old, with a sibling-matched donor, one can expect 70+% long-term survival. With those younger than 20 years of age, long-term survival is 90+%. For those 50 years of age or older, that percentage drops to 50%.^{1, 4}. Unrelated donors from registries with proper matching also provide good survival data but have far more graft versus host disease.¹

When BMT cannot be performed, advances in immunology have also been accruing. The combination of anti-thymocyte globulin, which has activity against the cytotoxic T lymphocytes, the immunosuppressive drug cyclosporin, and the stem-cell stimulant eltrombopag are increasing complete response rates to 50%.^1,5 These immunosuppressives can yield overall response rates to 80% without undue toxicity cost.⁶

Relapse rates and clonal deterioration into acute myeloid leukemia remain problematic compared to BMT, which remains the therapy of choice when available.² These therapeutics are in the domain of sub-specialists but demonstrate the capability of converting a diagnosis, which once meant certain death in the short-term into one which offers quite good prospects for many patients.

Patient follow-up. Considering the profound pancytopenia, urgent hematology consultation was requested. The peripheral blood smear revealed a paucity of platelets and WBC, most of which were mature lymphocytes. No abnormal cells (eg, immature or blast forms) were seen. A bone marrow biopsy was performed and revealed markedly decreased cellularity (less than 5% cells) with only plasma cells and lymphocytes seen.

There were inadequate numbers of cells either peripherally or on the marrow to perform flow cytometry or genomic testing. Further history was probed and was negative for either exposure to drugs/toxins or family history of blood disorders. The patient thus manifested all the criteria for severe aplastic anemia, namely less than 25% cellularity, absolute neutrophil count less than 500, and platelets less than 20,000.¹ This diagnosis and his young age made him a candidate for rapid BMT.

He acutely received antibiotics for his pharyngitis, which resulted in his being afebrile within 36 hours. He had two siblings, both of whom were HLA-compatible matches leading to an allogeneic hematopoietic stem cell transplantation. Results were excellent, with recovery of blood counts and no graft versus host disease complications. The patient is well and back in school 1 year later.

What’s The Take Home? Aplastic anemia is a rare and devastating entity resulting from destruction of hematopoietic stem cells in the marrow, which causes a profound pancytopenia peripherally with anemia, neutropenia, and thrombocytopenia. The low cell counts cause patient fatigue, spontaneous infections, and platelet-type bleeding (petechiae, ecchymoses, and mucosal bleeding). The three pathophysiologies that can cause this are (1) radiation/cytotoxic drug exposure, (2) genetic abnormalities in marrow stem cells (Fanconi syndromes), and (3) idiopathic immune mechanisms with destruction of stem cells by T lymphocytes. The latter is by far the most common form of aplastic anemia.

The diagnosis can be confirmed through bone marrow biopsy, but therapy alternatives include allogeneic BMT and immunosuppression/stem cell stimulant combinations. Transplantation is curative and the preferred therapy when feasible. Specifics of treatment are very specialized and usually performed at tertiary centers. The prognosis of acquired aplastic anemia was nearly 100% mortality in 1 year as recently as 50 years ago. Recent treatment methods have changed this to a 90+% cure for patients under 18 and 50% to 80% or more with long-term remissions in patients older than 18 years of age with continued improvement in those figures. Immunosuppressive techniques have also markedly improved with combinations offering 80% response rate and even 50% likely "cures" in patients who cannot undergo BMT.

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

CITATION
Rubin RN. A 20-Year-Old Man With A Severe Sore Throat And Fatigue. Consultant. 2023;63(9):e8. doi:10.25270/con.2023.08.000013.

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. Young NS. Aplastic Anemia. N Eng J Med. 2018;379:1643-1654
2. Hennohock Kelly HR, Meyerowitz EA, Friqault MJ,  Massoth LR. Case 31-2021. Case records of Massachusetts General Hospital. N Eng J Med. 2021; 385:1511-1520.
3. Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood. 2012;120:1185-1196.
4. Drexler B, Zurbeiggen F, Diesch T et al. Very long term follow up of aplastic anemia treated with marrow immunosuppressive therapy or allogeneic hemaopoietic cell transplantation. Ann Hematol. 2020;99:2529-2538
5. Townsley DM, Steinberg P, Winkler T et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Eng J Med. 2017;376:1540-1550
6. Bacigalupo A. How I treat acquired aplastic anemia. Blood. 2017;129:1428-1436

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