Coronavirus disease 2019 (COVID-19): Focus on peripheral blood cell morphology.

Numerous studies have shown peculiar morphological anomalies in COVID-19 patients' smears. We searched all the peer-reviewed scientific publications that explicitly reference the cytomorphological alterations on peripheral blood smears of patients with COVID-19. We extracted data from sixty-five publications (case reports, patient group studies, reviews, and erythrocyte morphology studies). The results show that frequent alterations concern the morphology of lymphocytes (large lymphocytes with weakly basophilic cytoplasm, plasmacytoid lymphocytes, large granular lymphocytes). Neutrophils display abnormal nuclei and cytoplasm in a distinctive cytomorphological picture. Besides a left shift in maturation, granulations can be increased (toxic type) or decreased with areas of basophilia. Nuclei are often hyposegmented (pseudo-Pelger-Huёt anomaly). Apoptotic or pycnotic cells are not uncommon. Monocytes typically have a large cytoplasm loaded with heterogeneous and coalescing vacuoles. Platelets show large and giant shapes. The presence of erythrocyte fragments and schistocytes is especially evident in the forms of COVID-19 that are associated with thrombotic microangiopathies. Such atypia of blood cells reflects the generalized activation in severe COVID-19, which has been demonstrated with immunophenotypic, molecular, genetic, and functional methods. Neutrophils, in particular, are involved in the pathophysiology of hyperinflammation with cytokine storm, which characterizes the most unfavorable evolution.

Peripheral Blood Examination Findings in SARS-CoV-2 Infection.

OBJECTIVES: Peripheral blood abnormalities in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been fully elucidated. We report qualitative and quantitative peripheral blood findings in coronavirus disease 2019 (COVID-19) patients and compare them with a control group. METHODS: We reviewed electronic medical records, complete blood counts, peripheral blood smears, and flow cytometry data in 12 patients with SARS-CoV-2. These were compared with 10 control patients with symptoms suspicious for SARS-CoV-2 but who tested negative. RESULTS: No significant differences were noted in blood counts, except that absolute lymphopenia was present frequently in the control group (P < .05). Acquired Pelger-Huët anomaly (APHA) was noted in all COVID-19 cases, in most cases affecting over 5% of granulocytes. This contrasted with APHA in only 50% of control cases, affecting fewer than 5% of granulocytes in all cases (P < .05). Monolobate neutrophils were exclusive to COVID-19 cases. COVID-19 patients had greater frequency of plasmacytoid lymphocytes (P < .05). Flow cytometry data revealed absolute CD3+ T-cell count reduction in 6 of 7 patients; all of them required mechanical ventilation. CONCLUSIONS: Lymphopenia was infrequent in our COVID-19 cohort; however, flow cytometric analysis revealed absolute T-cell count reduction in most cases. COVID-19 cases had significant APHA with monolobate neutrophils and plasmacytoid lymphocytes as compared to controls.

The Pseudo-Pelger HuËt Cell-A New Permanent Radiation Biomarker.

Using archival peripheral blood slides obtained from patients in the 1958 Y-12 criticality accident, the authors have recently described the pseudo-Pelger Huët anomaly (PHA) in neutrophils as a new radiation-induced biomarker. The current work provides additional evidence that PHA is also a permanent biomarker, potentially useful in retrospective dosimetry. In the Y-12 cohort, the high dose group (n = 5, 2.98-4.61 Gy-Eq) exhibited 13.0 ± 0.85 % Pelger Huët cells (mean ± SEM) in the neutrophil population compared to 6.8 ± 1.6 % in the low dose group (n = 3, 0.29-0.86 Gy-Eq; p = 0.008). An age and gender-matched control group (n = 8) exhibited 3.6 ± 0.9 % PH cells. Results of a one-way ANOVA show that the high dose group is statistically different from both the low dose group and the control group (p = 0.002). In the Y-12 cohort, PHA appears <12 h post-accident and is permanent for more than 16 y. Similar long-term persistence of the PHA mutation has been obtained from examination of peripheral blood slides from the 1971 Co accident at the Variable Dose Rate Irradiation Facility (VDRIF) in Oak Ridge, TN. In order to investigate the pseudo-PH cell as a biomarker in animal studies under well controlled dosimetry, peripheral blood slides were obtained from animals in a nonhuman primate (NHP) (Macaca mulatta) total-body irradiation (TBI) model (Co γ rays at 0.6 Gy min; dose range 1-8.5 Gy, LD50/60 6.44 Gy). In the NHP studies, the first measurement of PHA is taken at 5 h post-irradiation, then daily for days 1-5 and every 5-10 d thereafter. In the TBI model, the PH cell appears quickly (<5 h) post-irradiation, and the dose-dependent PH percentage is constant from 1 d over the 60-d monitoring period of the experiments. Using the average of data from 1-60 d, a linear dose response (PHA % slope = 0.49 ± 0.07 % Gy, r = 0.92) is obtained over the dose range 0-8.5 Gy. The authors conclude that ionizing radiation induces dose-dependent internuclear bridges in circulating neutrophils, and this morphological change can be used both as an acute phase biomarker and as a tool for retrospective dosimetry.

[Acquired Pelger-Huët anomaly/abnormal chromatin clumping of granulocytes after allogeneic hematopoietic stem cell transplantation for acute myeloid leukaemia: medication or relapse? ]. / Anomalie de Pelger-Huët acquise/condensation anormale de la chromatine des granulocytes après allogreffe médullaire pour leucémie aiguë myéloïde : iatrogène ou signe de rechute ?

An acute myeloid leukemia was diagnosed in a 53-year-old female patient. She received an allogeneic stem cell transplant. After this transplant, some neutrophils with hyposegmented nucleus and abnormal chromatin clumping appeared in the peripheral blood, and their number gradually increased. The hypothesis of early relapse after transplant was ruled out and drug-related anomaly was suspected. The authors discuss about morphological features of constitutional and acquired Pelger-Huët anomaly. In the patient reported here, ciclosporine seemed to be involved in the phenomenon, as the morphological anomaly of the neutrophils gradually decreased after the drug was discontinued.

NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina.

We report two unrelated patients with a multisystem disease involving liver, eye, immune system, connective tissue, and bone, caused by biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene. Both presented as infants with recurrent episodes triggered by fever with vomiting, dehydration, and elevated transaminases. They had frequent infections, hypogammaglobulinemia, reduced natural killer cells, and the Pelger-Huët anomaly of their granulocytes. Their facial features were similar with a pointed chin and proptosis; loose skin and reduced subcutaneous fat gave them a progeroid appearance. Skeletal features included short stature, slender bones, epiphyseal dysplasia with multiple phalangeal pseudo-epiphyses, and small C1-C2 vertebrae causing cervical instability and myelopathy. Retinal dystrophy and optic atrophy were present in one patient. NBAS is a component of the synthaxin-18 complex and is involved in nonsense-mediated mRNA decay control. Putative loss-of-function mutations in NBAS are already known to cause disease in humans. A specific founder mutation has been associated with short stature, optic nerve atrophy and Pelger-Huët anomaly of granulocytes (SOPH) in the Siberian Yakut population. A more recent report associates NBAS mutations with recurrent acute liver failure in infancy in a group of patients of European descent. Our observations indicate that the phenotypic spectrum of NBAS deficiency is wider than previously known and includes skeletal, hepatic, metabolic, and immunologic aspects. Early recognition of the skeletal phenotype is important for preventive management of cervical instability.

Appearance of pseudo-Pelger Huet anomaly after accidental exposure to ionizing radiation in vivo.

To evaluate the morphology of formed elements of human blood after exposure to ionizing radiation in vivo, archival smears of peripheral blood from eight individuals involved in the 1958 Y-12 criticality accident at Oak Ridge, Tennessee, were examined manually by light microscopy. For each case, increased interlobar bridging was observed in nuclei of the myeloid cells, many of which were bilobed and morphologically similar to Pelger Huet (PH) cells. The high-dose group (n = 5, 2.98-4.61 Gy-Eq) exhibited 13.0 ± 0.85% PH cells (mean ± SEM) in the neutrophil population compared to 6.8 ± 1.6% in the low-dose group (n = 3, 0.29-0.86 Gy-Eq; p = 0.008). An age- and gender-matched control group (n = 8) exhibited 3.6 ± 0.9% PH cells. Results of a one-way ANOVA show that the high-dose group is statistically different from both the low-dose group and the control group (p = 0.002). However, the low-dose group is not statistically different from the control group (p = 0.122). The mean number of nuclear lobes in blood neutrophils was also enumerated as a function of time after exposure and was found to be diminished, consistent with incomplete nuclear segmentation that is characteristic of the Pelger Huet anomaly (PHA). In contrast to these changes in myeloid cells, the morphology of erythrocytes and platelets appeared to be normal. The authors conclude that ionizing radiation induces abnormal morphology of circulating neutrophils, which is similar to the pseudo-PHA that is acquired in disorders such as myelodysplastic syndrome, acute myeloid leukemia, and leukemoid reactions. Potential molecular mechanisms by which radiation induces this morphological change are discussed. From this cohort, the biomarker appears to be present early post-accident (<9 h) and stable at least up to 16 y post-accident. Assessment of circulating pseudo-Pelger Huet cells is being investigated as a potential biodosimetric tool.

Pelger-huet anomaly and a mild skeletal phenotype secondary to mutations in LBR.

The Lamin B receptor (LBR) gene has been described to encode a bifunctional protein. Mutations in the LBR gene can affect neutrophil segmentation and sterol reductase activity and have been associated with two different recognized clinical conditions, Pelger-Huet anomaly (PHA) and Greenberg skeletal dysplasia. PHA is a benign autosomal co-dominant laminopathy resulting in bilobed neutrophil nuclei in heterozygotes, and unsegmented (ovoid) neutrophil nuclei in homozygotes. Some putative PHA homozygotes have been reported with minor skeletal malformations. Greenberg skeletal dysplasia is a severe autosomal recessive, perinatal lethal dwarfing disorder in which heterozygous carriers are usually without clinical manifestations. We here report a girl who has bilobed neutrophil nuclei and a mild skeletal dysplasia. Mutation analysis showed two novel mutations in the LBR gene: c.651_653 delinsTGATGAGAAA (p.Ile218Aspfs*19) and c.1757G > A (p.Arg586His). These mutations were found to be in trans, and, thus, she is a compound heterozygote. Sterol analysis found trace amounts of cholesta-8,14-dien-3beta-ol, which is normally undetected in healthy individuals. This and previously reported cases suggest that mutations in LBR can result in a continuum of phenotypic manifestations.

Pseudo-Pelger-Huët anomaly induced by medications: a clinicopathologic study in comparison with myelodysplastic syndrome-related pseudo-Pelger-Huët anomaly.

Pseudo-Pelger-Huët anomaly (PPHA) has been documented in association with transplant medications and other drugs. This iatrogenic neutrophilic dysplasia is reversible with cessation or adjustment of medications but is frequently confused with myelodysplastic syndrome (MDS) based on the conventional concept that PPHA is a marker for dysplasia. We investigated the clinicopathologic features in iatrogenic PPHA and compared them with MDS-related PPHA. The 13 cases studied included 5 bone marrow/stem cell transplantations, 3 solid organ transplantations, 1 autoimmune disease, 3 chronic lymphocytic leukemias, and 1 breast carcinoma. For 12 cases, there was follow-up evaluation, and all demonstrated at least transient normalization of neutrophilic segmentation. All 9 cases of MDS demonstrated at least 2 of the following pathologic abnormalities on bone marrow biopsy: hypercellularity (8/9), morphologic dysplasia (8/9), clonal cytogenetic abnormality (7/9), and increased blasts (3/9), whereas these abnormalities were typically absent in iatrogenic PPHA. Iatrogenic PPHA displayed a higher proportion of circulating PPHA cells than in MDS (mean, 47.4%; SD, 31.6% vs mean, 12.3%; SD, 9.8; P < .01). A diagnostic algorithm is proposed in which isolated PPHA is indicative of transient or benign PPHA unless proven otherwise.

Pseudo-Pelger-Huët in kidney-transplanted patients.

Pelger-Huët anomaly is an inherited condition characterized by hyposegmentation of the neutrophil nucleus and excessive chromatin clumping. Acquired Pelger-Huët, also known as pseudo-Pelger-Huët, has been described in several clinical conditions including transplant recipients who received immunosuppressive drugs. The incidence of pseudo-Pelger-Huët in kidney transplant patients, characterized as neutrophil dysplasia, was observed in 9 of 170 patients (5.3%) at the São Francisco Hospital de Assis, Belo Horizonte, Brazil. Awareness of possible circulating neutrophil alterations in transplant patients is important for laboratory professionals who should report these findings of cell changes. It should be highlighted that the poor segmentation and the chromatin hypercondensation observed initially in pseudo-Pelger-Huët patients can be suggestive of early-stage neutrophils. Only a combination of laboratory and clinical data will facilitate a better understanding of this anomaly and its correct follow-up and management.

Acquired Pelger-Huët anomaly in association with concomitant tacrolimus and mycophenolate mofetil in a liver transplant patient: a case report and review of the literature.

Pelger-Huët anomaly is a congenital or acquired abnormality of neutrophil nuclear segmentation. The acquired form may be a result of a clonal myeloid malignancy, such as myelodysplastic syndrome, or may be a secondary nonclonal change related to a variety of underlying causes, including infections and medications. We report a case of a 56-year-old man who developed acquired Pelger-Huët anomaly following liver transplantation while on the immunosuppressive agents tacrolimus and mycophenolate mofetil. These medications have been reported in association with this abnormality, but usually as a single agent or in combination with other drugs. In our case, the Pelger-Huët anomaly may be the result of the combination of these 2 drugs or mycophenolate alone with subsequent desensitization because resolution of the abnormality occurred after a reduction in mycophenolate mofetil dose, and the abnormality did not recur when mycophenolate mofetil was increased to a dose previously associated with Pelger-Huët anomaly during the time that tacrolimus was discontinued.

Pelgeroid-like anomalous cells in the diagnosis of neutrophilic dermatosis associated with myelodysplastic syndrome.

Neutrophilic dermatoses (ND), with or without accompanying myelodysplastic syndrome (MDS), were examined in terms of nuclear abnormality like pelgeroid anomaly of infiltrating cells into skin lesions. Six ND accompanying MDS showed 1.0 to 13.5% of such anomalous cells among infiltrating cells. In contrast, ND without accompanying myeloproliferative disorders rarely had such anomalous cells. Our findings suggest that pelgeroid-like anomalous cells infiltrating into ND are probably a good marker of underlying MDS.