Acquired Pelger-Huët anomaly in a patient treated with valganciclovir

Abstract

A follow-up blood count was performed on a 74-year-old woman diagnosed with colitis due to cytomegalovirus and under treatment with valganciclovir. The automated complete blood count revealed an abnormal white blood cells (WBC) scattergram together with WBC alert flags. The peripheral blood smear showed neutrophils with markedly hyposegmented nuclei or bilobed nuclei and very condensed chromatin or clumping chromatin all consistent with Pelger-Huët anomaly (PHA). We checked previous blood counts, ruling out an inherited PHA. We assessed the haematological, infectious and iatrogenic aetiologies for an acquired PHA. Once the valganciclovir treatment was completed and the drug was withdrawn, without changing the rest of the treatment, the morphological abnormalities of neutrophils were completely resolved. We conclude therefore that the acquired PHA presented by our patient is probably related to valganciclovir treatment.

Background

Pelger-Huët anomaly (PHA) is a morphological abnormality of leucocytes which was described as an autosomal dominant hereditary alteration by K Pelger in 1928.

Similar acquired morphological abnormalities, called acquired PHA (APHA) or pseudo-PHA, are present in haematological diseases (such as myelodysplastic syndromes, chronic myeloid leukaemia and acute myeloblastic leukaemia),¹ in reversible benign processes of infectious aetiology (such as HIV, tuberculosis, Mycoplasma pneumoniae and severe bacterial infection)² and also related to the use of drugs for transplant recipients (such as mofetil mycophenolate)³ and other drugs (valproate, sulfisoxazole, gancyclovir).² Thus, distinction between malign and non-malign aetiologies is very important from the diagnostic point of view.

Case presentation

A 74-year-old woman visited our laboratory to carry out an analysis requested by Internal Medicine for medical monitoring of a colitis due to cytomegalovirus (CMV) under medical treatment with valganciclovir. This CMV infection was diagnosed by immunohistochemistry in an ileum and right colon biopsy.

A routine blood count was performed on a haematology analyser (Sysmex XN de Roche), which showed a white blood cells (WBC) alteration due to a variation in the neutrophil scattergram. The white differential flourescent scattergram shows the distribution of the different WBC populations, depending on its side scattered light (SSC) and side fluorescent light characteristics. In our case, this scattergram showed an abnormal cluster at first glance. Additionally, it presented a suspicion alarm of blasts and immature granulocytes. Together with the above results, we observed an important increase of the numerical values (range 561–735) of the NE-WY (neutrophils fluorescence intensity and the width of dispersion) and decrease (range 143–157) of the NE-SSC (neutrophils cell complexity), markedly different from the previous analyses that were within the normal range.⁴

Peripheral blood smear revealed neutrophils presenting markedly hyposegmented nuclei or bilobed nuclei, and others with lobular, oval or round nuclei and highly dense nuclear chromatin or clumping chromatin (abnormal agglomeration of nuclear chromatin, large blocks of chromatin by clear areas) that can be described as Pelger-Huët morphology (figure 1). The rest of the blood cells did not present any alterations.

Figure 1.

Blood smear and white blood cell scattergram evolution.

Previous diagnoses were moderate sleep apnoea–hypopnoea syndrome, rheumatoid arthritis treated with methotrexate, deflazacort and weekly abatacept, middle lobe syndrome with cylindrical bronchiectasis and loss of volume, bronchial hyper-reactivity and cardiac insufficiency. The patient was also under treatment with folic acid, lidocaine patches, denosumab, calcium–vitamin D, esomeprazole, ranitidine, furosemide and lormetazepam.

The patient continued with this treatment and valganciclovir (900 mg every 12 hours × 3 weeks) was added. As the patient maintained immunosuppression, it was then recommended to continue prophylaxis for 6 months with valganciclovir 900 mg every 24 hours.

Over the 4 months of treatment, laboratory test results showed the same morphological features described.

Investigations

As we described in the previous section, the peripheral blood smear showed neutrophil alterations that can be qualified as PHA (figure 1).⁵

The blood count obtained 10 days after the beginning of treatment was retrospectively revised, showing normal numerical parameters without any morphological alarm.

Cytological diagnosis

Acquired PHA or pseudo-PHA is probably related to viral infection or to valganciclovir treatment.

Outcome and follow-up

Consecutive blood counts obtained 5 and 6 months after the beginning of valganciclovir treatment showed the same alarms and the same morphological alteration in the blood smear, although blood PCR for CMV was negative. Analysis carried out 1 month after finishing valganciclovir treatment showed that a blood count without alarms and morphology on peripheral blood smear was normal, persisting normal 4 months later (see figures 1 and 2). Therefore, we conclude that this morphological alteration is probably due to treatment with valganciclovir.

Figure 2.

Blood counts: 1, pretreatment; 2–5, under treatment; 6 and 7, after withdrawal of treatment (1 month and 4 months, respectively).

Discussion

Our case highlights the importance of distinguishing between PHA and APHA. Well-prepared and stained blood smears, shortly after venipuncture, are essential to distinguish between both aetiologies. If prepared 12 hours later, the smear could show degenerated neutrophils with picnotic round nuclei. It is also essential to evaluate thoroughly the morphology of all blood cells.

The presence of hyposegmentated nuclei may cause diagnostic confusion with band neutrophils or left shift and generate unnecessary diagnostic and therapeutic interventions.

PHA is an inherited anomaly with an autosomal-dominant pattern. The neutrophils show dumbbell-shaped bilobed nuclei, a reduced number of nuclear segments and coarse clumping of the nuclear chromatin. The overall cell size, appearance of cytoplasm and staining quality of granules in PHA cells are similar to normal mature neutrophils. In case of suspicion, we should perform a family morphological study and review previous blood counts of the patient.

APHA is an acquired alteration of neutrophils resembling PHA. There are two major aetiologies of acquired granulocytic changes:

1. Neoplastic. We must rule out myelodysplastic syndrome (MDS) or myeloid-related neoplasm (MPM) because APHA is a marker of myelodysplasia. These cases are characterised by morphological heterogeneity of nuclei, without symmetry, and affecting less than 25% of granulocytes.⁶ Hypogranular neutrophils are common and chromatin is not very clumped. Platelets and red blood cells can also be morphologically abnormal.

2. Non-neoplastic, drug-related or infectious. Usually the main related drug is mofetil mycophenolate in transplanted patients. In these cases, the changes disappear 2–6 weeks after treatment cessation.⁷ Sometimes the changes return to normal without any change in relevant drugs, suggesting desensitisation or tolerance to drugs. Other drugs related to APHA are tacrolimus, fluconazole or rituximab, alone or in combination with mofetil mycophenolate. There are some reports of APHA associated with the use of acyclovir, ganciclovir⁸ and valganciclovir,⁹ latter used in our patient.

The pathogenesis of hereditary PHA is related to an alteration in B-lame receptor, an internal nuclear membrane protein.⁵ The pathogenesis of APHA is unknown, but the cases of antiviral treatment could be related to DNA polymerase inhibition during DNA synthesis.

Learning points.

• The acquired Pelger-Huët abnormality is present in haematological diseases such as myelodysplastic syndromes, chronic myeloid leukaemia and acute myeloblastic leukaemia.

• It is also present in reversible benign processes of infectious aetiology or related to the use of drugs for transplant recipients (as mofetil mycophenolate).

• Distinction between malign and non-malign etiologies is very important from the diagnostic point of view.