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Πέμπτη 14 Οκτωβρίου 2021

The Substantial Omission of Postoperative Radiotherapy in Patients With Advanced-Stage Oral Cancer

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This cohort study aims to identify factors associated with omission of adjuvant postoperative radiotherapy in patients with advanced-stage oral squamous cell cancers in the US.
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Acute Vision Loss From IgG4-Related and Bacterial Rhinosinusitis After COVID-19

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This case report describes a man in his 70s who presented to the emergency department with a headache for 2 weeks and vision loss in the right eye for 2 days and was subsequently diagnosed with IgG4-related and Streptococcus constellatus rhinosinusitis.
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Continuous Local Anesthetic Wound Infusions as Postoperative Standard of Care in Patients With Head and Neck Cancer

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To the Editor We thank Gostian et al for their study demonstrating a reduction in postoperative pain when continuous wound infusion (CWI) was used after head and neck oncological resections. The authors call for CWI to be assimilated into the multimodal postoperative analgesic concept in patients. However, prior to widespread implementation, we find it prudent to draw attention to a few caveats to the study's conclusions.
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Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer

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This systematic review and meta-analysis assesses the efficacy and safety of neoadjuvant immunotherapy for resectable head and neck squamous cell carcinoma.
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Symptoms With New Loss of Taste or Smell in Adults With or Without SARS-CoV-2 Infection

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There have been reports of loss of taste or smell associated with viral infections, including SARS-CoV-2. However, it is not clear whether these symptoms are more frequent in SARS-CoV-2 infection compared with other viral infections.1,2 Prior studies among individuals with SARS-CoV-2 infection suggest loss of taste or smell occurs early in the disease course and is associated with younger age, female sex, and milder disease.1,3-5 Those studies largely have not examined which symptoms occur with new loss of taste or smell. Identifying concomitant symptoms may guide future studies to identify a pattern of symptoms that form a unique clinical presentation. We therefore described which symptoms were reported with new loss of taste or smell among individuals with and without SARS-CoV-2 infection.

Methods
Data for this cross-sectional study were collected from the Centers for Disease Control and Prevention's Coronavirus Self-checker (online since March 2020), an online tool designed to assist users in deciding whether to seek testing or medical care per guidelines from possible SARS-CoV-2 exposure.6 Users selected hard-coded responses that included demographics (age, sex, race, ethnicity), any COVID-19 test results within the past 10 days (positive, negative), and symptoms (new loss of taste or smell, muscle aches or body aches, cough, mild or moderate difficulty breathing, fever, vomiting or diarrhea, headache, congestion or runny nose, sore throat, other). Vaccination status was not recorded. The sample included 59 153 completed uses of the tool occurring between February 2 and May 3, 2021, by US adults 18 years or older who reported test results. This study was reviewed by the Centers for Disease Control and Prevention (CDC), and its conduct was consistent with applicable feder al law and CDC policy (45 CFR §46, 21 CFR §56, 42 USC §241(d), 5 USC §552a, and 44 USC §3501 et seq). This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

To evaluate the association between each symptom and new loss of taste or smell, multivariate logistic models estimated odds ratios (ORs) stratified by test positivity and adjusted for each demographic variable and symptom. For all statistical analyses, SAS, version 9.4 software (SAS Institute Inc) was used.

Results
The Table shows respondent characteristics from 59 153 completed uses of the tool. The largest age group was 18 to 29 years (15 792 [26.7%]), 38 798 (65.6%) were female, and 37 025 (62.6%) were non-Hispanic White respondents. Symptoms associated with new loss of taste or smell varied by SARS-CoV-2 test positivity (Figure). Among individuals with negative test results, congestion or runny nose was more strongly associated with loss of taste and smell (OR, 2.26 [95% CI, 2.08-2.45]) compared with those with positive test results (OR, 1.66 [95% CI, 1.54-1.79]). Among individuals with negative test results, cough and fever were significantly associated with new loss of taste or smell (cough: OR, 1.57 [95% CI, 1.45-1.69]; fever: OR, 1.16 [95% CI, 1.07-1.25]) but not among those with positive test results (cough: OR, 1.01 [95% CI, 0.94-1.09]; fever: OR, 0.95 [95% CI, 0.88-1.02]). Vomiting or diarrhea was more strongly associated with new loss of taste or smell among those with posit ive test results (OR, 1.52 [95% CI, 1.40-1.65] compared with those with negative test results (OR, 1.23 [95% CI, 1.13-1.35]).

Discussion
The findings of this cross-sectional study suggest that differences in symptoms occurring with new loss of taste or smell were seen between groups based on SARS-CoV-2 test positivity. In both groups, muscle aches or body aches, mild or moderate difficulty breathing, vomiting or diarrhea, and congestion or runny nose were associated with a new loss of taste or smell. However, in both groups with positive and negative test results, congestion or runny nose had strong associations with new loss of taste or smell, suggesting the latter may not be a valid marker of test positivity in this sample.

One particular strength of this study is the large sample of recent data. Limitations include possible residual confounding inherent in observational data and potential for data to partially reflect individuals who used the tool multiple times and/or had been vaccinated. There may also be selection bias from analyzing online data, as respondents were, on average, younger and more likely to be female compared with the general population. Users may also have been aware of loss of taste or smell as a symptom of COVID-19, which may have resulted in bias and/or loss of power. Further studies in other populations may elucidate whether symptoms accompanying a new loss of taste or smell may form part of a unique clinical presentation associated with a milder course of disease.

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This cross-sectional study uses data from the Centers for Disease Control and Prevention's Coronavirus Self-checker to assess which symptoms are reported with new loss of taste or smell among individuals with and without SARS-CoV-2.
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Evaluation of the Neuroanatomical Basis of Olfactory Dysfunction

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Key Points
Question What are the neuroanatomical correlates of olfactory function in the general population?

Findings In this cross-sectional study of 541 participants who underwent brain imaging and olfactory assessment, olfactory bulb volume was independently associated with olfactory function and a robust mediator of the association between volumes of central olfactory structures (amygdala, hippocampus, insular cortex, and medial orbitofrontal cortex) and olfactory function.

Meaning Olfactory dysfunction may primarily originate from the pathology of the olfactory bulb or more distal structures, whereas olfactory bulb volume may serve as a preclinical marker for the identification of individuals who are at an increased risk for developing neurodegenerative diseases later in life.

Abstract
Importance Olfactory dysfunction is a prodromal manifestation of many neurodegenerative disorders, including Alzheimer and Parkinson disease. However, its neuroanatomical basis is largely unknown.

Objective To assess the association between olfactory brain structures and olfactory function in adults 30 years or older and to examine the extent to which olfactory bulb volume (OBV) mediates the association between central olfactory structures and olfactory function.

Design, Setting, and Participants This cross-sectional study analyzed baseline data from the first 639 participants with brain magnetic resonance imaging (MRI) in the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany. Participants were enrolled between March 7, 2016, and October 31, 2017, and underwent brain MRI and olfactory assessment. Data were analyzed from March 1, 2018, to June 30, 2021.

Exposure Volumetric measures were derived from 3-T MRI T1-weighted brain scans, and OBV was manually segmented on T2-weighted images. The mean volumetric brain measures from the right and left sides were calculated, adjusted by head size, and normalized to all participants.

Main Outcomes and Measures Performance on the 12-item smell identification test (SIT-12) was used as a proxy for olfactory function.

Results A total of 541 participants with complete data on MRI-derived measures and SIT-12 scores were included. This population had a mean (SD) age of 53.6 (13.1) years and comprised 306 women (56.6%). Increasing age (difference in SIT-12 score, –0.04; 95% CI, –0.05 to –0.03), male sex (–0.26; 95% CI, –0.54 to 0.02), and nasal congestion (–0.28; 95% CI, –0.66 to 0.09) were associated with worse olfactory function (SIT-12 scores). Conversely, larger OBV was associated with better olfactory function (difference in SIT-12 score, 0.46; 95% CI, 0.29-0.64). Larger volumes of amygdala (difference in OBV, 0.12; 95% CI, 0.01-0.24), hippocampus (0.16; 95% CI, 0.04-0.28), insular cortex (0.12; 95% CI, 0.01-0.24), and medial orbitofrontal cortex (0.10; 95% CI, 0.00-0.20) were associated with larger OBV. Larger volumes of amygdala (volume × age interaction effect, 0.17; 95% CI, 0.03-0.30), parahippocampal cortex (0.17; 95% CI, 0.03-0.31), and hippocampus (0.21; 95% CI, 0.08-0. 35) were associated with better olfactory function only in older age groups. The age-modified association between volumes of central olfactory structures and olfactory function was largely mediated through OBV.

Conclusions and Relevance This cross-sectional study found that olfactory bulb volume was independently associated with odor identification function and was a robust mediator of the age-dependent association between volumes of central olfactory structures and olfactory function. Thus, neurodegeneration-associated olfactory dysfunction may primarily originate from the pathology of peripheral olfactory structures, suggesting that OBV may serve as a preclinical marker for the identification of individuals who are at an increased risk of neurodegenerative diseases.

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This cross-sectional study evaluates the role of the components of the olfactory pathway structures in impaired olfactory function.
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A Not-So-Simple Thyroid Nodule

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A 50-year-old woman presented with a 2-month history of a neck mass that was associated with hoarseness of voice and globus sensation. Physical examination showed thyromegaly (right greater than left) with an approximately 5-cm palpable nodule in the right lobe. There was no tenderness or cervical lymphadenopathy. There was no prior radiation exposure to the head and neck area. Thyroid function test results were normal, and she did not take thyroid medications. A relative had received a diagnosis of papillary thyroid cancer at age 50 years. There was no other pertinent family history, including a history of multiple endocrine neoplasia. Ultrasonography results showed a multinodular goiter with a dominant 4.6-cm right thyroid nodule, 1.6-cm left-sided thyroid nodule, and suspect left level IV lymph node. Ultrasonography-guided fine-needle aspiration biopsy results showed papillary thyroid carcinoma (PTC ) (Bethesda VI) with a BRAFV600E variation in the left nodule and lymph node, and atypia of undetermined significance (Bethesda III) with a suspicious Afirma genomic sequence classifier in the right nodule. She underwent total thyroidectomy with modified left lateral neck dissection. Gross examination of the specimen showed a 2.9-cm pale-tan, partially circumscribed, soft nodule in the right thyroid lobe; a 1.4-cm pale-tan, fibrotic, centrally brown nodule in the left lobe; and a 1.8-cm pale-tan, rubbery, partially circumscribed nodule in the isthmus. Histologic examination of the right thyroid lesion was performed (Figure), with ancillary testing.

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A 50-year-old woman presents with a 2-month history of a neck mass that was associated with hoarseness of voice and globus sensation and thyromegaly with a palpable nodule in the right lobe. What is your diagnosis?
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Evaluation of Nocturnal Enuresis After Adenotonsillectomy in Children With Obstructive Sleep Apnea

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This secondary analysis of a randomized clinical trial of children who underwent adenotonsillectomy for nonsevere obstructive sleep apnea evaluates the prevalence of nocturnal enuresis after the operation.
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Neck Mass in an Adolescent......

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A 13-year-old male presented to the pediatric otolaryngology clinic with a 2-year history of a right neck mass that had slowly increased in size. He denied any associated symptoms of pain, fevers, chills, malaise, night sweats, unintentional weight loss, prior history of neck masses, recent upper respiratory tract infections, or skin lesions. He was the product of a full-term pregnancy with up-to-date immunizations. Physical examination revealed a 2.5-cm firm, ovoid, mobile, and nontender mass at the apex of the posterior triangle of the right neck without any associated overlying skin changes. The remainder of the head and neck examination was unremarkable. Doppler ultrasonography revealed a 1.9 × 1.8 × 0.9-cm hypoechoic mass, and subsequent fine-needle aspirates demonstrated cells with elongated nuclei and eccentric blue cytoplasm in a background of myxoid stroma. The mass was excised in en tirety without issue. At the time of surgery, the deep surface of the mass was found to be adherent to the sternocleidomastoid muscle. The lesion was resected with a cuff of muscle and sent for permanent histopathological examination. This revealed proliferation of bland spindle cells with plump nuclei and eosinophilic cytoplasm arranged as loose fascicles in a background of myxoid stroma (Figure 1). These cells were positive for mucin 4 (MUC4), epithelial membrane antigen (EMA), and transducing-like enhancer of split 1 (TLE1) immunohistochemical stains. Fluorescence in situ hybridization (FISH) revealed a positive FUS (16p11) gene rearrangement.


A t(7;16)(q34;p11) translocation, yielding a FUS/CREB3L2 fusion gene, has been identified in approximately 80%-90% of deep soft tissue LGFMS.https://pubmed.ncbi.nlm.nih.gov/21399449/

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This case report describes a 13-year-old male who presented with a 2-year history of a right neck mass that had slowly increased in size. What is your diagnosis?
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Olfactory Bulb Volume—A Novel Preclinical Biomarker for Smell Loss and Neurodegenerative Disease

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Neurodegenerative disorders, such as Alzheimer dementia and Parkinson disease, are disabling diseases that present a burden on society that rivals the costs of cancer and heart disease. Although current therapies are often unsuccessful at reversing the progression of these diseases, early detection in patients who are at risk of neurodegenerative disease could allow for timely interventions to delay and minimize the loss of brain function over time.
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Placement of a Double-Lumen Endotracheal Tube

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Case 31-2021: A 21-Year-Old Man with Sore Throat, Epistaxis, and Oropharyngeal Petechiae

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Presentation of Case
Dr. Philippe-Antoine Bilodeau (Medicine): A 21-year-old man presented to this hospital with a sore throat, epistaxis, and petechiae of the oropharynx.

One week before the current presentation, blood-filled blisters developed inside the patient's mouth, on the buccal mucosa. He had occasional bleeding from the mouth that resolved spontaneously. He consulted with his dentist, who was concerned about the possibility of impacted wisdom teeth. Two days before the current presentation, a sore throat developed. There was no difficulty with swallowing. On the day of the current presentation, epistaxis developed and did not resolve over a period of 2 hours.

Table 1.

Laboratory Data.
The patient presented to another hospital for evaluation. On examination, the temperature was 37.1°C, the blood pressure 142/76 mm Hg, the pulse 98 beats per minute, the respiratory rate 16 breaths per minute, and the oxygen saturation 99% while he was breathing ambient air. He had blood in the nares and petechiae on the soft palate. There was a large ecchymosis on the left forearm that the patient attributed to carrying heavy boxes several days earlier. The remainder of the examination was normal. Laboratory testing revealed a hemoglobin level of 9.8 g per deciliter (reference range, 13.5 to 17.5), a platelet count of 1000 per microliter (reference range, 150,000 to 450,000), and a white-cell count of 670 per microliter (reference range, 4000 to 11,000). The absolute neutrophil count was 50 per microliter (reference range, 1800 to 7000). Blood levels of electrolytes and glucose were normal, as were results of tests for coagulation, renal function, and liver function. Other laborato ry test results are shown in Table 1. The nose was packed to control the bleeding, and 1 unit of platelets was transfused. The patient was transferred to this hospital for additional evaluation and treatment.

In the emergency department of this hospital, the patient reported a mild sore throat but no other symptoms; epistaxis had resolved with nasal packing. There was no fever, weight loss, rash, nausea, vomiting, or diarrhea. The patient had a history of sickle cell trait. He took no medications and had no known allergies. He had been living with his parents and younger brother since he had left his college campus at the start of the coronavirus disease 2019 (Covid-19) pandemic. He worked in a grocery store, and his only known sick contact was his mother, who had been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 2 months earlier. She had been isolated in a room in their home during her illness. The patient did not have any symptoms associated with Covid-19 and had never been tested for SARS-CoV-2 infection. His father and brother had been well. The family lived adjacent to a wooded region, and the patient had been hiking in northern New England 2 months befo re the current presentation. He had not noticed any tick bites. He had no animal contacts. The patient was born in Central America and had moved to a suburban region of New England at 3 years of age. He had previously traveled to Mexico and Canada. He was sexually active with female partners only. He did not smoke tobacco, drink alcohol, or use illicit drugs. His father had hypertension and hyperlipidemia, and paternal family members had sickle cell disease.

Figure 1.

Clinical Photograph.
On examination, the patient appeared well. There were petechiae on the soft palate (Figure 1). There was no scleral icterus, lymphadenopathy, or hepatosplenomegaly. A large ecchymosis was present on the left forearm. The remainder of the examination was normal. Blood levels of folate and cobalamin were normal, as were results of serum protein electrophoresis and the ratio of free kappa to lambda light chains. Other laboratory test results are shown in Table 1. A radiograph of the chest and an ultrasound image of the upper abdomen were normal, without splenomegaly. Testing of a specimen obtained from the nasopharynx was positive for SARS-CoV-2 RNA; the patient was admitted to the hospital and placed in enhanced isolation. Examination of thick and thin peripheral-blood smears for babesia was negative.

A second unit of platelets was transfused, and a diagnostic test was performed.

Differential Diagnosis
Dr. Hanno Hock: I participated in the care of this patient, and I am aware of the diagnosis. This 21-year-old man had been in excellent health until the week of admission, when oropharyngeal and cutaneous bleeding developed. On presentation, the severely decreased platelet count explained the bleeding. The very low total white-cell count and absolute neutrophil count indicated that he was at risk of infection. The only moderately decreased hematocrit suggested that he did not have long-standing severe anemia, but the absence of reticulocytes showed that red-cell production was profoundly impaired. Because he tested positive for SARS-CoV-2 RNA, could this patient's cytopenias be related to SARS-CoV-2 infection?

Patients with SARS-CoV-2 infection and an acute febrile illness often have blood abnormalities such as pancytopenia,1-3 which are sometimes triggered by hemophagocytic lymphohistiocytosis.4,5 However, this patient did not have a febrile illness. In the absence of illness, his positive SARS-CoV-2 test could be indicative of the presymptomatic incubation period of SARS-CoV-2 infection, asymptomatic active infection, or shedding of RNA after asymptomatic infection. However, none of these circumstances have been associated with major blood abnormalities. Therefore, we needed to consider the wide spectrum of causes of pancytopenia.

SICKLE CELL TRAIT
This patient did not use medications, illicit drugs, or alcohol and had normal levels of vitamin B6 and vitamin B12. These features rule out several common causes of cytopenia. Patients with sickle cell disease are at risk for aplastic crisis, which is an acute decrease in the red-cell count that often occurs after parvovirus B19 infection.6 This patient was a carrier of sickle cell trait but was not at risk for the major complications of sickle cell disease.7 Although sickle cell trait is associated with some health risks8 and should be considered as a potential factor contributing to poor outcomes among Black patients with Covid-19,9 it has not been linked to pancytopenia.7

INCREASED CELL DESTRUCTION
Pancytopenia can result from several conditions that cause increased cell destruction. Cells may pool in an enlarged spleen or be destroyed by the splenic reticuloendothelial system, but this patient did not have splenomegaly. Evans syndrome — a combination of immune thrombocytopenic purpura, autoimmune hemolytic anemia, and immune neutropenia — causes pancytopenia from peripheral destruction.10 Immune thrombocytopenic purpura has recently been reported in association with Covid-19.4 However, this patient did not have evidence of hemolysis or compensatory reticulocytosis, which would be expected in a patient with Evans syndrome. Hemophagocytic lymphohistiocytosis can be triggered by numerous infectious agents other than SARS-CoV-2, including Epstein–Barr virus and cytomegalovirus,5 but this patient did not have signs of infection or inflammation.

DECREASED CELL PRODUCTION
Infection can impair cell production through various mechanisms.11,12 Parvovirus B19,13 hepatitis C virus,14 human herpesvirus 6,15 human herpesvirus 7,16 cytomegalovirus,17 and the human immunodeficiency virus (HIV)18 can directly infect hematopoietic stem cells and progenitor cells. Cytomegalovirus, HIV, and coxsackievirus B can infect bone marrow stromal cells and suppress cell production,11 but this usually occurs in patients who have a chronic condition, take an immunosuppressive medication, or have overt signs of infection. Many pathogens suppress cell production indirectly, through cytokine release and inflammation.11 Respiratory viruses such as influenza A, influenza B, rhinovirus, and SARS-CoV-2 can cause transient cytopenias in ill patients, but this patient did not have a fever and was otherwise well.1,19

CANCER
Lymphoma, myeloma, leukemia, and myelodysplastic syndromes can cause pancytopenia by replacing normal hematopoietic stem cells with malignant cells. Leukemia can be aleukemic, without leukemic blasts in the blood. The presentation of myelodysplastic syndromes in children and young adults may be different from that in older adults; younger patients more often have hypocellular bone marrow, which makes it harder to differentiate the condition from aplastic anemia.20-23 In addition, paroxysmal nocturnal hemoglobinuria, a clonal disorder that initially manifests as hemolytic anemia because of complement-mediated destruction, may cause pancytopenia in the late stages.24 However, the absence of constitutional symptoms, sudden onset of bleeding, and nearly complete absence of cell production made cancer and paroxysmal nocturnal hemoglobinuria unlikely diagnoses in this case.

APLASTIC ANEMIA
Aplastic anemia is characterized by pancytopenia and the loss of hematopoietic stem cells, progenitor cells, and precursor cells in the bone marrow.25,26 It was the most likely diagnosis in this previously healthy patient with pancytopenia in the absence of constitutional symptoms and abnormal cells. Aplastic anemia results from one of three main mechanisms25: damage by extrinsic factors, manifestations of familial genetic mutations, and autoimmune attack on hematopoietic stem cells and progenitor cells.

Extrinsic causes of aplastic anemia are usually obvious and include major accidental or therapeutic exposure to radiation, chemotherapy, or massive exposure to benzene25 or pesticides such as organochlorines and organophosphates.27 Several medications have been infrequently associated with aplastic anemia.27,28 However, this patient was not taking any medications and had no known chemical or radiation exposures.

The genetic disorder most commonly associated with aplastic anemia is Fanconi's anemia, a DNA repair defect that results from a mutation in 1 of at least 15 known genes.29 Patients with Fanconi's anemia typically have bone marrow failure in the first or second decade of life, as well as other congenital abnormalities, including thumb and facial deformities and short stature.29 The second most common genetic cause of bone marrow failure is dyskeratosis congenita, which is due to mutations in genes involved in telomere repair or protection.30 Dyskeratosis congenita typically manifests in childhood with skin pigmentation abnormalities, oral leukoplakia, and dystrophic nails. However, the disease may cause isolated bone marrow failure.31 Finally, GATA2 mutations have emerged as a potential genetic cause of aplastic anemia.32 These mutations are associated with other manifestations, including lymphedema, generalized warts from human papillomavirus infection, and mycobacterial infectio n.23 This patient's pancytopenia was unlikely to be caused by a congenital genetic abnormality because he had no family history of such a condition and no associated signs or symptoms.

Up to 70% of cases of aplastic anemia occur sporadically, resulting from the sudden onset of T-cell–mediated destruction of hematopoietic stem cells and progenitor cells.28 Most cases of aplastic anemia are designated as idiopathic because the triggers for the immune attack on hematopoiesis are obscure. There are known associations with thymoma33 and eosinophilic fasciitis.34 However, both these diseases develop predominantly in the seventh decade of life, and this patient did not have the widened mediastinum on chest radiography that is suggestive of thymoma or the dimpled skin thickening (peau d'orange change) that is suggestive of eosinophilic fasciitis.34

The most common known trigger for aplastic anemia is seronegative hepatitis, which precedes 5 to 10% of cases of aplastic anemia by approximately 2 to 3 months.35,36 The median age at the onset of hepatitis-associated aplastic anemia is 20 years, but this patient's history did not suggest recent hepatitis. Aplastic anemia is also thought to occur after infection with common hepatitis viruses37 and other viruses, including HIV and parvovirus B19,12,38,39 but at a much lower frequency than with seronegative hepatitis.

It is intriguing that this patient's exposure to SARS-CoV-2 and probable asymptomatic infection occurred 2 months before his presentation, an interval similar to that between the onset of seronegative hepatitis and the development of aplastic anemia; therefore, it is tempting to speculate that SARS-CoV-2 infection may have been a trigger. However, his presentation and age also fit with idiopathic aplastic anemia, which has an incidence of 2 to 3 cases per 1 million per year.27 Given the scale of the Covid-19 pandemic, a potential association may eventually be confirmed if the incidence of aplastic anemia rises. Regardless of the trigger, this patient's presentation and blood abnormalities were highly suggestive of aplastic anemia, a diagnosis that must be confirmed with evidence of markedly reduced hematopoiesis in a bone marrow–biopsy specimen. The severity of aplastic anemia is determined by the degree of the associated peripheral-blood cytopenias.28,40,41 The near absence of platelets, neutrophils, and reticulocytes in this case was associated with a high risk of death and a very low chance of recovery without urgent treatment and consideration of bone marrow transplantation.

Dr. Hanno Hock's Diagnosis
Severe aplastic anemia in the presence of infection with severe acute respiratory syndrome coronavirus 2.

Diagnostic Testing
Figure 2.

Peripheral-Blood and Bone Marrow Specimens.
Dr. Lucas R. Massoth: Examination of a peripheral-blood smear confirmed the presence of severe leukopenia and thrombocytopenia. Most of the white cells were lymphocytes, including plasmacytoid forms, and there were rare plasma cells (Figure 2A). The neutrophils were morphologically normal. Results of flow cytometric studies of the peripheral blood, including tests for paroxysmal nocturnal hemoglobinuria and telomere length analysis, were unremarkable.

An aspirate and a core biopsy specimen of the bone marrow were obtained. The aspirate was paucicellular and composed of peripheral-blood elements. The core biopsy specimen (Figure 2B and 2C) showed markedly hypocellular marrow (<5% cellularity) for the patient's age and was composed mainly of lymphocytes and plasma cells. Maturing hematopoietic elements were rare, and reticulin fibrosis was absent. Immunohistochemical stains used to detect proteins expressed by herpes simplex virus types 1 and 2, cytomegalovirus, and parvovirus B19 were negative. Chromogenic in situ hybridization studies used to detect RNA of Epstein–Barr virus and SARS-CoV-242 (Figure 2D) were also negative.

Flow cytometric studies of the bone marrow aspirate showed no abnormal lymphoid or myeloblast population. Cytogenetic studies failed to obtain metaphases for analysis, most likely because of low specimen cellularity. Targeted next-generation sequencing was negative for mutations commonly associated with hematologic cancer, including predisposing germline variants.

The overall findings of pancytopenia and severe trilineage bone marrow hypoplasia were most consistent with a diagnosis of acquired aplastic anemia. Although circulating plasmacytoid lymphocytes and plasma cells are not characteristic of aplastic anemia, their presence has been documented after various infections, including SARS-CoV-2 infection.43 The absence of detectable SARS-CoV-2 RNA on in situ hybridization argues against the possibility that intramedullary infection had led to bone marrow injury.

Pathological Diagnosis
Severe acquired aplastic anemia.

Hospital Course
Dr. Bilodeau: While the results of the bone marrow biopsy were pending, filgrastim and eltrombopag were administered. On hospital day 5, the sore throat worsened and fever developed, with a temperature of 38.2°C. An oral examination showed persistent petechiae and leftward deviation of the uvula. There was mild tenderness of the anterior aspect of the neck on the right side. Laboratory test results are shown in Table 1. Imaging studies were obtained, and intravenous cefepime and vancomycin were administered.

Figure 3.

CT Scan of the Neck.
Dr. Hillary R. Kelly: Computed tomography of the neck (Figure 3), performed after the administration of intravenous contrast material, revealed marked enlargement of the right palatine tonsil. There was a surrounding hypoattenuating abnormality in the right peritonsillar space that was most consistent with phlegmon or edema. These changes were causing partial airway effacement. There was no evidence of a well-defined rim-enhancing peritonsillar abscess.

Dr. Bilodeau: The patient's sore throat improved 48 hours after the administration of intravenous antibiotic agents, and bone marrow transplantation was considered.

Discussion of Management
Dr. Eric A. Meyerowitz: It was necessary to determine whether this patient had active SARS-CoV-2 infection. The presence of active infection would have major implications regarding the safety of bone marrow transplantation.

SARS-CoV-2 infection can be either symptomatic or asymptomatic. Asymptomatic infection occurs when a person has none of the many symptoms attributable to SARS-CoV-2 throughout the course of infection.44,45 This patient had a sore throat and fever on hospital day 5, which could have been consistent with the onset of symptoms. However, he had focal tenderness on the right side of the neck and phlegmon on imaging that responded well to the prompt administration of intravenous antibiotics. This response was most consistent with a pharyngeal bacterial infection in the presence of neutropenia.

Since the household is the most common site of viral transmission, we suspected that the patient had been infected with SARS-CoV-2 approximately 2 months earlier, when his mother had a confirmed infection; community transmission was uncontrolled at that time.46 In immunocompetent adults, viable SARS-CoV-2 can be recovered until approximately 10 days after the onset of mild disease and 20 days after the onset of severe disease.47 Viral replication occurs in the respiratory tract of infected persons; after an incubation period, the viral load increases rapidly, peaking within 3 days after it starts to rise, and then begins to decline.48 Although active viral replication occurs over a relatively short period, viral RNA is often detected well after this period, with a median duration of nasopharyngeal RNA shedding of 22 days in immunocompetent hosts with mild disease.49 Therefore, a positive nucleic acid test may indicate either the presence of replicating virus (a finding diagnostic of active infection) or RNA shedding (a finding consistent with either very early infection or late, resolving infection) but cannot be used to distinguish between these clinical scenarios.

My approach to interpreting the positive SARS-CoV-2 test in this patient involved estimating where he was in the course of infection. Tracking the cycle threshold (Ct) value is an indirect but evidence-based method to assess for viable virus. The Ct value is the number of cycles required to amplify viral RNA to a level at which it can be detected by the assay. It is inversely correlated with the viral load. Many SARS-CoV-2 nucleic acid tests use a Ct value as a cutoff; if the patient's Ct value is below the cutoff, the test is considered to be positive. Most commercially available assays that use Ct values typically undergo approximately 40 cycles. For each patient, serial testing should be performed at a single laboratory. A first test with a Ct value of less than 30 is a strong predictor of acute infection.48 Two tests separated by at least 2 days with Ct values of 30 or more suggest that early infection, whether primary infection or reinfection, is unlikely.48,50-53 This patient had a positive SARS-CoV-2 test with a Ct value of 38 on admission and had another positive test with a Ct value of 35 on hospital day 6; on both tests, only one of two targets was amplified, which highlighted the profoundly low level of viral RNA present. These Ct values have not been associated with active viral replication in the extensive literature published to date.

In putting this information together, our assessment was that this patient was a previously immunocompetent young man who had a history of persistent asymptomatic SARS-CoV-2 infection, which was currently in a state of prolonged RNA shedding, without evidence of replication-competent virus. On the basis of these findings, I thought that the patient could safely undergo bone marrow transplantation and was considered to have a very low risk of additional complications from SARS-CoV-2 infection.

Dr. Matthew J. Frigault: Management of aplastic anemia depends on the severity of illness, the patient's age, the availability of an appropriate stem-cell donor, and the presence of coexisting conditions that could limit the patient's ability to undergo allogeneic stem-cell transplantation.26 This patient met the criteria for severe aplastic anemia, which are a bone marrow cellularity of less than 25% and at least two of the following features: an absolute neutrophil count in peripheral blood of less than 500 per microliter, a platelet count of less than 20,000 per microliter, or a reticulocyte count of less than 20,000 per microliter. This patient also met the criteria for very severe aplastic anemia, because his absolute neutrophil count was less than 200 per microliter.

Other than stem-cell transplantation, standard intensive approaches include combination immunosuppressive therapy. Although this approach is promising, rates of relapse and clonal evolution to myelodysplastic syndrome or acute myeloid leukemia are often higher in patients treated with immunosuppressive therapy alone than in those treated with stem-cell transplantation, with rates of failure-free survival beyond 10 years of less than 50% in some series.54 For this reason, the use of allogeneic stem-cell transplantation in medically fit patients with appropriate stem-cell donors has increased.55 Traditional risks associated with allogeneic stem-cell transplantation include graft failure and graft-versus-host disease; the risk of graft-versus-host disease depends on the degree of HLA disparity, the sex of the donor, the intensity of transplantation conditioning, and the graft source.56

This patient had a 16-year-old brother who was a complete match, and because the brother had robust fitness and did not have any precluding conditions, we elected to pursue stem-cell transplantation with the brother as the donor. The risks of transplantation have been substantially reduced through advances in the use of alternative donor sources and in strategies for the prevention of graft-versus-host disease. In two recent series that evaluated the use of nonmyeloablative conditioning with a post-transplantation regimen of cyclophosphamide in combination with tacrolimus and mycophenolate mofetil in patients with severe aplastic anemia who received stem-cell transplants from bone marrow grafts of matched related and unrelated donors, overall survival at 2 years was nearly 100% and graft-versus-host disease–free survival was more than 84%.57,58 For this patient, we proceeded with upfront allogeneic stem-cell transplantation.

Despite the challenges of a recent SARS-CoV-2 infection, with close collaboration from our infectious disease colleagues, we were able to begin transplantation in the patient within 28 days after the initial presentation. Now, 1 year after transplantation, he has full donor chimerism and a complete hematologic response. He has had no evidence of acute or chronic graft-versus-host disease. The patient is completing college coursework and working part time, and he went skydiving to celebrate his 1-year anniversary of completing transplantation.

Final Diagnosis
Severe acquired aplastic anemia after infection with severe acute respiratory syndrome coronavirus 2.

This case was presented at the Medical Case Conference.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank Dr. Valentina Nardi for her review of the pathological discussion and Dr. Niyati Desai for the performance of SARS-CoV-2 in situ hybridization.

Author Affiliations
From the Departments of Medicine (H.H., M.J.F.), Radiology (H.R.K.), and Pathology (L.R.M.), Massachusetts General Hospital, the Departments of Medicine (H.H., M.J.F.), Radiology (H.R.K.), and Pathology (L.R.M.), Harvard Medical School, and the Department of Radiology, Massachusetts Eye and Ear (H.R.K.) — all in Boston; and the Department of Medicine, Montefiore Medical Center, New York (E.A.M.).

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