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Year : 2022  |  Volume : 11  |  Issue : 5  |  Page : 21-23

Interstitial lung disease with congenital erythrocytosis

1 Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
2 Department of Haematology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
3 Department of Radiodiagnosis, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India

Date of Submission30-Oct-2020
Date of Decision17-Jan-2021
Date of Acceptance25-May-2021
Date of Web Publication30-Aug-2022

Correspondence Address:
D T Katyarmal
Associate Professor, Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati 517 507, Andhra Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCSR.JCSR_93_20

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A 45-year-old male weaver, smoker, known case of interstitial lung disease with cor pulmonale on long-term oxygen therapy diagnosed 6 months ago who is on tapering doses of oral steroids presented to our tertiary care teaching hospital with complaints of worsened shortness of breath, cough with expectoration and fever for the past 4 days. The patient had headache, dizziness for the past 6 months. On examination, he was febrile with plethoric facies, conjunctival congestion and digital clubbing were noted. Tachycardia and tachypnoea were noted. Haemoglobin saturation on pulse oximetry was 75% while breathing on room air, 94% with 0.4 fraction of inspired oxygen. On respiratory system examination, bilateral infraaxillary crepts were present, jugular venous pressure was elevated. Remaining systemic examination was unremarkable. Investigations revealed elevated haemoglobin, elevated leucocyte count with neutrophilic leucocytosis, raised packed cell volume and red cell count. Platelet count 1.67 × 105/mm3, erythrocyte sedimentation rate 4 mm at the end of the first hour. Computed tomography (CT) of the chest (plain) showed inter and intralobular septal thickening with honeycombing in the bilateral lower lobes predominantly features suggestive of interstitial lung disease. Ultrasonography of the abdomen showed no hepatosplenomegaly. Two dimensional echocardiography was suggestive of corpulmonale. As patient had hyperviscosity symptoms due to polycythaemia and no improvement in haemoglobin with supplemental oxygen for the past 6 months, patient was further evaluated for alternate cause of polycythaemia. Serum erythropoietin (Epo) levels were normal. Arterial oxygen tension at which oxygen saturation was 50% (P50) was 28 mm Hg. Epo gene receptor mutation was positive suggestive of congenital erythrocytosis. Patient was advised long-term oxygen therapy and regular therapeutic phlebotomy to maintain haemoglobin levels and was discharged in a haemodynamically stable condition.

Keywords: Congenital erythrositosis, interstetial lung disease, polycythemia

How to cite this article:
Katyarmal D T, Haneesha M, Bhargav K M, Chandrasekhar C, Vijayalakshmi B, Mounika N. Interstitial lung disease with congenital erythrocytosis. J Clin Sci Res 2022;11, Suppl S1:21-3

How to cite this URL:
Katyarmal D T, Haneesha M, Bhargav K M, Chandrasekhar C, Vijayalakshmi B, Mounika N. Interstitial lung disease with congenital erythrocytosis. J Clin Sci Res [serial online] 2022 [cited 2022 Dec 7];11, Suppl S1:21-3. Available from: https://www.jcsr.co.in/text.asp?2022/11/5/21/355066

  Introduction Top

Interstitial lung disease (ILD) comprises a large and heterogeneous group of disorders that often lead to progressive fibrosis and premature death. An injured lung as a result of infection, inhalation of chemical and other harmful substances either resolves over time or progresses into irreversible damage and fibrosis.[1] Secondary polycythaemia may develop in patients with chronic hypoxic lung disease as a result of compensatory mechanisms probably induced by a reduction in arterial oxygen saturation measured by pulse oximetry (SpO2).[2]

  Case Report Top

A 45-year-old male weaver, agricultural labourer presented to medicine outpatient service with chief-complaints of cough for 1 year, which was productive in nature. He was producing moderate quantities of sputum that was mucoid inconsistency and was not foul smelling. He also complained of dyspnoea for 6 months that was insidious in onset, gradually progessive with no seasonal, diurnal or postural variation. There was no history of wheeze. On general physical examination the atient was conscious, oriented; afebrile. Pulse was 106/min, regular. Blood pressure (BP) was 120/80 mm Hg in the right arm in sitting position. SpO2 measured by while breathing room air, was 82%. Digital clubbing was present. He had no icterus, cyanosis, pedal oedema or generalised lymphadenopathy. Systemic examination-respiratory system revealed normal vesicular breath sounds in both lungs; velcro crepitations were heard in both lung bases. Other systems examination was unremarkable. Laboratory testing revealed high haemoglobin (20.7 g/dL), elevated total leucocyte count (10,500 cell/mm3) with neutrophilic leucocytosis (neutrophils 82%), high packed cell volume (PCV) (62%) and red cell count (5.7 millions/mm3), platelet count 1.64 × 105/mm3 and erythrocyte sedimentation rate 4 mm at the end of the first hour.

Immunofluorescence for antinuclear antibodies (ANAs) tested negative by indirect immunofluorescence. Cytoplasmic antineutrophil cytoplasmic autoantibodies (cANCA), perinuclear antineutrophil cytoplasmic autoantibodies (pANCA), anti glomerular basement membrane antibodies tested negative. Chest radiograph showed increased reticular markings in bilateral basilar regions. High-resolution computed tomography (HRCT) of the chest showed interlobular interstitial thickening noted bilateral lung predominantly in the peripheral zones suggestive of ILD [Figure 1]. Spirometry was suggestive of restrictive lung pattern. The patient was treated with intravenous methylprednisolone (1 g od for 3 days), followed by tapering course of oral prednisolone 1 mg/kg/day for 6 weeks.
Figure 1: High resolution computed tomography of chest showing bilateral ground glass opacities predominantly in peripheral zones

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Patient improved symptomatically. He was advised home oxygen therapy and formoterol, budesonide metered dose inhaler. On the next admission, patient presented in the emergency department with complaints of high grade intermittent fever for 1 week, associated with chills and rigors, cough with expectoration that mucoid inconsistency, non-foul smelling and not associated with haemoptysis. He also complained of dyspnoea for 2 weeks that was acute in onset. There was no history of wheeze. On general examination the patient was febrile (temperature 101 °F), pulse 121/min, blood pressure 100/60 mm of Hg, respirations 36/min. The SpO2 was 72% on room air. Use of accessory muscles of respiration was evident. Diffuse coarse crepitations were heard all over the chest. Laboratory Investigations revealed elevated haemoglobin, elevated leucocyte count with neutrophilic leucocytosis, raised packed cell volume and red cell count. Platelet count 1.67 × 105/mm3, erythrocyte sedimentation rate 4 mm at the end of the first hour. In view of hyperviscosity symptoms and high haemoglobin level with elevated haematocrit (Hct), workup for polycythaemia was done. Ultrasonography of abdomen was normal. Two dimentional echocardiography did not reveal any evidence of the right to left shunt. Serum erythropoietin (Epo) levels were normal (6 IU/L). Arterial oxygen tension at which oxygen saturation was 50% (P50) was 28 mm Hg. As Epo levels were normal, secondary polycythaemia was ruled out. Further workup for congenital polycythemia was carried out. Genetic analysis by polymerase chain reaction amplification and deoxyribonucleic acid (DNA) sequencing for Epo receptor (Epo r) gene, von Hippel Lindau (VHL) and Janus kinase 2 mutation were done. Epo r gene muatation was found to be positive.

  Discussion Top

ILD is characterised by inflammation and/or fibrosis of the lung parenchyma. Some forms of ILD are irreversible, characterised by progressive hypoxaemia. Patients with advanced ILD frequently develop hypoxaemia due to multiple physiologic derangements, including diffusion limitation, ventilation-perfusion mismatching, and abnormalities of the pulmonary vasculature erythrocytosis is a response to hypoxaemia, it is rarely reported in patients who have chronic pulmonary diseases. It is due to an increase in plasma volume coexisting with the increase in red cell mass (RCM). In ILD, it was reported that <5% of the patients develop erythrocytosis. However, information is scarce.[3] In contrast, a study[4] done in Mexican population showed that half of the patients with interstitial pulmonary fibrosis had high haematocrit values. The frequent finding of high haematocrit values may be the result of severe hypoxaemia due to an interaction of lung disease and high altitude. Epo is the principal regulator of proliferation and differentiation of erythroid cells.[4] The synthesis of Epo by the kidneys is under the control of a feedback mechanism where low oxygen tension stimulates Epo production, thereby increasing erythroid cell production. Epo mediates its biological activity by binding to specific cell surface receptors on erythroid cells. Six mutations of the human Epo R have been reported to be associated with erythrocytosis.[5]

Absolute polycythemia refers to an increase in RCM. The World Health Organization (WHO) criteria for diagnosis of polycythaemia are: Increased haemoglobin (>16.5 g/dL in men or >16.0 g/dL in women), increased haematocrit (>49% in men or >48% in women).[6] Primary polycythaemia is caused by acquired (somatic) or inherited (germline) mutations expressed within the erythroid progenitors that increase their proliferation and cause accumulation of erythrocytes (i.e., polycythemia). Such mutations occur in polycythemia vera and in dominantly inherited polycythemias caused by “gain-of-function” mutations of the Epo r gene.[7] Secondary polycythemia refers to conditions in which there are circulating plasma factors that stimulate erythropoiesis. Secondary polycythemia can be “appropriate” or “inappropriate” physiological responses. Examples include appropriate physiological response to tissue hypoxia. Examples of inappropriate responses include EPO-secreting tumours or increased erythropoetin secretion due to congenital disorders of hypoxia sensing.[8] Mixed (i.e., primary and secondary) congenital disorders of hypoxia sensing Some disorders share features of both primary (i.e., increased sensitivity of erythroid progenitors to erythropoetin) and secondary polycythemia (i.e., elevated erythropoetin levels). Examples include Chuvash polycythaemia, other congenital VHL gene mutations, and gain-of-function mutations of Endothelial PAS domain-containing protein 1 (EPAS1). Primary familial and congenital polycythaemia (PFCP) is characterised by isolated erythrocytosis in an individual with a normal-sized spleen and the absence of disorders causing secondary erythrocytosis.[9] About twenty pathogenic variants have been described in association with PFCP with most common located in exon 8, which encodes the C-terminal negative regulatory domain of the protein. Pathogenic variants are mostly non-sense or frameshift variants (due to small intragenic deletions or insertions) that predict or result in cytoplasmic truncation of the receptor and loss of the C-terminal negative regulatory domain.[10]

In normal physiology, EPO is the primary drive of red blood cell mass. Ninety percent of circulating EPO in humans is produced by the kidneys in response to hypoxia. Polycythemia may be encountered as an incidental abnormality on a complete blood count (CBC) and differential or in the course of evaluating other clinical findings. The urgency of evaluation is influenced by the presence of medical emergencies related to polycythemia (e.g., cerebrovascular accident and chest pain) and the level of haemoglobin/haematocrit.

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Conflicts of interest

The authors are faculty members/Postgraduate students/ residents of Sri Venkateswara Institute of Medical Sciences, Tirupati, of which Journal of Clinical and Scientific Research is the official Publication. The article was subject to the journal's standard procedures, with peer review handled independently of these faculty and their research groups.

  References Top

Johannson KA, Pendharkar SR, Mathison K, Fell CD, Guenette JA, Kalluri M, et al. Supplemental oxygen in interstitial lung disease: An art in need of science. Ann Am Thorac Soc 2017;14:1373-7.  Back to cited text no. 1
Spivak JL. Polycythemia vera: Myths, mechanisms, and management. Blood 2002;100:4272-90.  Back to cited text no. 2
Gallo RC, Fraimow W, Cathcart RT, Erslev AJ. Erythropoietic response in chronic pulmonary disease. Arch Intern Med 1964;113:559-68.  Back to cited text no. 3
Livingstone JL, Lewis JG, Reid L, Jefferson KE. Diffuse interstitial pulmonary fibrosis a clinical, radiological, and pathological study based on 45 patients. Q J Med 1964;33:71-103.  Back to cited text no. 4
Furukawa T, Narita M, Sakaue M, Otsuka T, Kuroha T, Masuko M, et al. Primary familial polycythaemia associated with a novel point mutation in the erythropoietin receptor. Br J Haematol 1997;99:222-7.  Back to cited text no. 5
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Fourth edition. Lyon: International Agency for Research on Cancer (IARC); 2017.  Back to cited text no. 6
Smith JR, Landaw SA. Smokers' polycythemia. N Engl J Med 1978;298:6-10.  Back to cited text no. 7
Aitchison R, Russell N. Smoking--A major cause of polycythaemia. J R Soc Med 1988;81:89-91.  Back to cited text no. 8
Al-Sheikh M, Mazurier E, Gardie B, Casadevall N, Galactéros F, Goossens M, et al. A study of 36 unrelated cases with pure erythrocytosis revealed three new mutations in the erythropoietin receptor gene. Haematologica 2008;93:1072-5.  Back to cited text no. 9
Huang LJ, Shen YM, Bulut GB. Advances in understanding the pathogenesis of primary familial and congenital polycythaemia. Br J Haematol 2010;148:844-52.  Back to cited text no. 10


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