B.Namratha Sai Reddy, Nishith Vaddeboina, Ch.Shyny Reddy

1Department of Medical Oncology, Omega Hospitals, Hyderabad, Telangana 500034, India.

Abstract Differentiation syndrome is a complication commonly encountered in acute promyelocytic leukemia patients when treated with Al-Trans retinoic acid.This Differentiation syndrome has very close similarities clinically and radiologically to SARS-CoV2 pneumonitis which makes diagnosis of differentiation syndrome challenging specially during this COVID-19 pandemic.We hereby report a case of a 68-year-old male with acute promyelocytic leukemia who on initiation of Al-Trans retinoic acid developed acute respiratory distress with radiological findings of multiple ground glass opacities in bilateral lungs suggestive of SARS-CoV2 pneumonitis.Considering the radiological similarities to differentiation syndrome and on high clinical suspicion, this patient was immediately started on steroids with which he recovered rapidly.During this pandemic of SARS-CoV2, distinguishing differentiation syndrome from SARS-CoV2 pneumonitis clinically and radiologically is extremely challenging.

Keywords: differentiation syndrome; SARS-CoV2 pneumonitis; leukemia

Background

Acute promyelocytic leukemia (APML) is a subtype of Acute myeloid leukemia with the predominance of immature granulocytes named promyelocytes.APML has the characteristic morphology of reciprocal chromosomal translocation of (15; 17) (q22; q12–q21).The unique feature of APML is its response to Al-trans-retinoic acid (ATRA) and one of the complications of treatment with ATRA in APML is development of differentiation syndrome (DS).DS is a multisystem disorder characterized by shortness of breath, fever, weight gain, hypotension and high permeability of pulmonary microcirculation.This condition is commonly seen in patients with APML, after the administration of ATRA at a rate of 2%–27% [1].

SARS-CoV2 pneumonia presents with upper and lower respiratory tracts symptoms like fever, cough, dyspnea and radiological imaging findings suggesting ground-glass opacities in bilateral lung fields.As this presentation is very similar to DS, distinguishing both is a challenge.The mortality of SARS-CoV2 pneumonia ranges between 0.2% and 15%, depending on age, underlying diseases, comorbidities, secondary bacterial infection, and timely diagnosis and treatment of the disease [2].The overall mortality attributed to DS is approximately 1% [3].

Because of the life-threatening nature of the DS, preemptive use of corticosteroids at the very earliest symptom or sign suggestive of DS has been recommended as the standard management [4].Temporary discontinuation of ATRA or arsenic trioxide (ATO) is indicated only in the case of DS with a very poor clinical condition or severe organ dysfunction.Otherwise, these differentiating agents could be maintained unless progression to overt syndrome or lack of response to dexamethasone is observed [4].

This is a case report of DS with clinical and radiological presentation similar to SARS-CoV2 pneumonitis.Informed consent was obtained from the patient for the case to be studied and published.

Case report

A 68-year-old man presented to our center with chief complaints of fever and easy bruisability for 10 days.On admission, complete hemogram showed white blood cells count of 590 cells/mm3, platelet count of 9,000 cells/mm3, hemoglobin of 7.7 g/dl.Peripheral smear showed circulating atypical cells constituting 21%.

Bone marrow aspiration and biopsy showed marked prominence of promyelocytes and morphological features consistent with Acute leukemia, favoring APML.Fluorescence in situ Hybridisation (FISH) for PML-RARA fusion was sent for confirmation of APML.

As the bone marrow studies were consistent with APML, the patient was started on ATRA 45 mg/m2 in 2 divided doses.After 2 days of initiation of ATRA, the patient developed fever, respiratory distress, hypoxemia.HRCT chest was performed which showed patchy ground-glass opacities in bilateral lungs -CORADS 5 (COVID-19 Reporting and Data System).Clinically suspicion of DS was high, the patient was started immediately on Intravenous dexamethasone 10 mg/m2 twice daily.Within 24 hours of initiation of steroids, the patient showed dramatic clinical improvement with significant resolution of the symptoms.Meanwhile RT-PCR for COVID-19 was performed to rule out SARS-CoV2 infection which turned out to be negative.His follow-up CT chest suggested a significant decrease in ground-glass opacities in bilateral lungs.

FISH for PML-RARA (t (15; 17) (q22; q12)) translocation was positive and hence Arsenic trioxide 0.15 mg/m2 IV was added to ATRA with tapering of steroids.

Discussion

DS, also formerly known as a retinoic acid syndrome, can occur when patients with APML (APL) are treated with the differentiating agents all-trans retinoic acid and arsenic trioxide [5].DS is a common complication in the treatment of APL with a reported incidence ranging from 2% to 48% [6].

The Montesinos criteria include the following key signs and symptoms: dyspnea, unexplained fever, weight gain greater than 5 kg, unexplained hypotension, acute renal failure and a chest radiograph demonstrating pulmonary infiltrates or pleural or pericardial effusion.The presence of three or more features is sufficient for a confident clinical diagnosis of DS [3].

The pathogenesis of DS involves cascade of events which: (1) lead to a release of cytokines by differentiating blast cells and (2) induce a change in adhesive properties on blasts cells.A variety of Pro-inflammatory cytokines, including interleukin (IL)1 beta, IL6, IL8 and tumor necrosis factor-alpha are released, which triggers an inflammatory response causing systemic inflammatory response syndrome [7].The release of cathepsin G increases vascular permeability and causes endothelial damage which also contributes to the alveolar damage [8].The combination of this intense systemic inflammation with increased vascular permeability and endothelial damage results in capillary-leak syndrome, acute respiratory distress syndrome (ARDS), hypotension and organ hypoperfusion, which can ultimately lead to multi-organ failure [8, 9].

The pathogenesis of the SARS-CoV2 infection is very similar to ATRA syndrome with the infection triggering an aggressive immune and inflammatory response leading to rapid release of a large amount of cytokines such as tumor necrosis factor-α, IL-1, IL-6 and interferon-γ causing cytokine storm which in turn results in diffuse alveolar damage, ARDS and multiorgan failure [10].

The clinical presentation SARS-CoV2 pneumonitis include fever, upper respiratory tract symptoms, anosmia, loss of taste, myalgias in mild to moderately severe cases and acute respiratory distress, hypotension and multiorgan failure in very severe cases.Whereas DS manifests as unexplained fever, weight gain, pleural effusions, hypoxemia, hypotension and can lead to ARDS and multiorgan if not managed early.

Radiographic findings like ground-glass opacity, consolidation, nodular opacities and pleural effusion seen in DS are also seen in COVID-19 pneumonia or other lung infections [11, 12].Chest CT abnormalities in SARS-CoV2 pneumonitis are usually bilateral, with lower lobes preference and peripheral distribution.Other less common findings include pleural effusion, hilar lymphadenopathy, crazy paving pattern, cavitation, interlobular septal thickening and linear opacities [13].

This patient was started on corticosteroids on clinical suspicion of DS in spite of the discouraging evidence of early use of steroids in SARS-CoV2pneumonitis.But this patient has shown dramatic response to steroids both clinically and radiologically, emphasizing that high clinical suspicion of DS and early treatment with steroids could be life saving specially during the covid-19 pandemic.

Conclusion

SARS-CoV2 pneumonitis is a deadly infection with mortality rates as high as 15%.The mortality rates of DS are as low as 1% with excellent clinical recovery rates when identified early.Hence, during the SARS-CoV2 pandemic, distinguishing DS from SARS-CoV2 pneumonitis clinically and also with the help of CT scan of the chest and microbiological correlation with RT-PCR for SARS-CoV2 is very essential.This report emphasizes that high clinical suspicion of DS in APML patients is required and early treatment with steroids is life saving specially during the COVID-19 pandemic.

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