Idiopathic pulmonary haemosiderosis misdiagnosed as haemolytic anaemia: a case report

Abstract

Idiopathic pulmonary haemosiderosis is a rare disease primarily affecting children. The condition is characterized by widespread bleeding from alveolar capillaries, resulting in symptoms such as haemoptysis, shortness of breath and iron deficiency anaemia. However, it is not a specific disease and sometimes can manifest solely as anaemia, which may be easily overlooked and misdiagnosed. The purpose of this case report was to describe a 1-year-old boy who exhibited haemolytic anaemia as the only symptom of idiopathic pulmonary haemosiderosis, with the intention of offering clinical insights into the precise diagnosis and subsequent management of this rare and easily misdiagnosed disease. Clinicians should keep idiopathic pulmonary haemosiderosis in mind when evaluating children with haemolytic anaemia and promptly initiate testing and treatment to prevent misdiagnosis and improve outcomes.

Introduction

Idiopathic pulmonary haemosiderosis is a rare disease with recurrent intrapulmonary haemorrhages. ¹ In select paediatric populations, the incidence of idiopathic pulmonary haemosiderosis varies between 0.24 and 1.26 patients per million, with a mortality rate of up to 50%. ² The aetiology and pathogenesis of the disease are currently unknown, but they may be related to autoimmune, environmental and genetic predisposing factors. ³ Typically, the disease manifests as a triad of haemoptysis, pulmonary infiltrates and iron deficiency anaemia. The rarity and non-specific presentation of the disease often result in a high rate of misdiagnosis. This current report describes a case of idiopathic pulmonary haemosiderosis with haemolytic anaemia as the only manifestation. The child was admitted to hospital several times and the diagnosis was confirmed through haemosiderin staining and a chest computed tomography (CT) scan.

Case report

In May 2022, a 1-year-old male was initially admitted to the Department of Paediatric Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu Province, China because of experiencing a pallid-yellow face for 1 week and pale red urine on one occasion more than 10 days prior to admission. The child had a poor appetite and was pallid after consuming diesel 1 week before admission. There were no observable fever or chills, abdominal pain or diarrhoea, nausea or vomiting, or significant improvement after treatment with ‘XiaoErXiShiTangJiang’ at a local clinic. Two days before this current admission, the child went to Tan Chang County Traditional Chinese Medicine Hospital, Longnan, Gansu Province, China. Whilst there, blood analysis showed the following: a leukocyte count of 9.1610 × 10⁹/l; a neutrophil ratio of 0.31; a lymphocyte ratio of 0.64; a red blood cell count of 2.4110 × 10¹²/l; a haemoglobin level of 62 g/l; a platelet count of 287 × 10⁹/l. Blood biochemistry showed the following: direct bilirubin of 11 µmol/l; indirect bilirubin of 28.90 µmol/l; total bilirubin of 39.90 µmol/l; a triad of anaemia with a folic acid level of >24 ng/ml. Routine urinalysis showed protein 3+ and occult blood 1+. Based on the patient's history and these pre-hospital admission examinations, the child was initially diagnosed with ‘anaemia’. The physical examination at the Department of Paediatric Gastroenterology, Lanzhou University Second Hospital showed pale lid conjunctiva, wan lips, congested pharynx and coarse breath sounds on auscultation of both lungs. The results of the initial laboratory tests are presented in Table 1.

Table 1.

Laboratory analyses for a 1-year-old male who was initially admitted because of experiencing a pallid-yellow face for 1 week and pale red urine on one occasion more than 10 days before admission.

Parameter	Value	Normal range
Lactic acid, mmol/l	3.6	0.5–2.2
White blood cell count, ×109/l	7.4	5.1–14.1
Haemoglobin, g/l	55	107–141
Red blood cell count, ×1012/l	2.2	4–5.5
Platelet count, ×109/l	430	190–524
C-reactive protein, mg/l	<9.99	<9.99
Urea, mmol/l	8.28	2.30–6.70
Potassium K, mmol/l	4.03	4.2–5.9
Total bilirubin, µmol/l	29.4	<26
Direct bilirubin, µmol/l	5.3	<4.0
Indirect bilirubin, µmol/l	24.1	0–22.1
Reticulocyte absolute value, ×109/l	318.6	24–84
Reticulocyte percentage, %	0.148	0.005–0.0015
Procalcitonin, ng/ml	0.22	0–0.046
β2 glycoprotein, reactive units/ml	36.77	<20
Folic acid, ng/ml	>20	4.2–19.8
Copper, mmol/l	27.1	10.99–21.98

The following tests were not abnormal: glucose-6-phosphate dehydrogenase (G6PD) gene test; thalassaemia gene; erythrocyte sedimentation rate test; complete set of infectious diseases; peripheral blood smear (outpatient); routine stool analyses; anti-cardiolipin antibody + anti-nucleosome antibody (ACA+ANuA); urine dry chemical analysis; anti-double-stranded DNA antibody (anti-dsDNA); antineutrophil cytoplasmic autoantibodies (ANCA) group set; anti-nuclear antibody test (ANA); ANA profile (blotting); anti-cyclic citrullinated peptide antibody (anti-CCP antibody) test; coombs test; copper blue protein test; routine urine analyses; two-factor test for Mycobacterium tuberculosis. An orthopantomogram digital radiography (DR) of the chest revealed no significant abnormalities in the heart, lungs or diaphragm (Figure 1a). An abdominal ultrasound showed no abnormalities in the liver, bile, pancreas, spleen or kidneys. Cardiac ultrasound indicated no abnormalities of intracardiac structures, tricuspid regurgitation (small amount), no abnormalities of cardiac function and no significant abnormalities of pulmonary artery pressure. Routine electrocardiography showed sinus tachycardia with a non-deviating cardiac axis and an approximately normal electrocardiogram.

Figure 1.

Chest X-rays and computed tomography (CT) of a 1-year-old male that was initially admitted because of experiencing a pallid-yellow face for 1 week and pale red urine on one occasion more than 10 days before admission: (a) the first chest radiograph undertaken during the first hospitalization (between 29 May 2022 and 2 June 2022) showed no significant abnormalities in the heart, lungs or diaphragm; (b) the second chest radiograph undertaken during the second hospitalization (between 27 June 2022 and 29 June 2022) showed increased lung texture in both lungs; (c) the third chest radiograph undertaken during the third hospitalization (between 21 February 2023 and 2 March 2023) showed no significant abnormalities in the heart, lungs or diaphragm and (d) chest CT scan during the third hospitalization (between 21 February 2023 and 2 March 2023) showed diffuse alveolar exudate in both lungs.

During this initial hospitalization between 29 May 2022 and 2 June 2022, a diagnosis of acute haemolytic anaemia was made based on the following: (i) anaemia; (ii) elevated indirect bilirubin; (iii) markedly elevated reticulocyte count; (iv) an out-of-hospital routine urine analysis showing protein 3+ and occult blood 1+; (v) the child's resolution of pale red urine on one occasion more than 10 days before hospital admission. As a consequence of this diagnosis, the child received 11 mg methylprednisolone every 12 h by intravenous drip for 4 days and 11 mg omeprazole once a day by intravenous drip for 4 days; as well as 500 mg calcium carbonate D3 granules orally once a day orally for 4 days and 1.46 g potassium citrate granules once a day orally for 4 days. The child's symptoms improved significantly during the initial hospitalization and 10 mg prednisone orally was continued for 1 week after discharge on 2 June 2022, with a weekly decrease of 5 mg until it was discontinued. All oral medication was stopped as of 16 June 2022. After the child's hospital discharge, haemolysis tests were performed (Table 2).

Table 2.

Haemolysis tests for a 1-year-old male who was initially admitted because of experiencing a pallid-yellow face for 1 week and pale red urine on one occasion more than 10 days before admission.

Parameter	Value	Normal range
Alkali resistant haemoglobin, %	0	0–2.5
Minor fraction of adult haemoglobin, %	2.6	2–3.5
Microhaemoglobin electrophoresis	No abnormal bands	No abnormal bands
Isopropanol	(–)	(–)
Methaemoglobin reduction test, %	84	>75
G6PD fluorescent spot assay	Visible fluorescence	Visible fluorescence
Heinz body, %	15	<30
Inclusion body H	(–)	(–)
Erythrocyte osmotic fragility test (start haemolysis), g/l	4.4	3.8–4.6
Erythrocyte osmotic fragility test (complete haemolysis), g/l	3.2	3.8–4.6
FLAER-negative cells, %	0.03%	>1
CD55 (red blood cell surface), %	97.22	>90
CD55 (granulocyte surface), %	99.94	>90
CD59 (red blood cell surface), %	99.92	>90
CD59 (granulocyte surface), %	99.94	>90

On 27 June 2022, the child was readmitted to the Department of Paediatric Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu Province, China due to a fever. Before admission, the child's temperature was 39.8°C. After taking antipyretic medication, the child's temperature dropped to a normal level. However, after 4–6 h, the fever returned without any other accompanying symptoms. The results of laboratory tests undertaken at that time are presented in Table 3. No obvious abnormalities were seen on Epstein–Barr virus and cytomegalovirus tests. An orthopantomogram DR of the thorax revealed increased lung texture (Figure 1b). Based on the symptoms and examination results, a diagnosis of ‘herpetic pharyngitis’ was made because the haemoglobin did not significantly decrease compared with normal values. The child received 110 mg potassium sodium dehydroandroan drographolide succinate once a day by intravenous drip for 3 days and this improved their condition. The child was discharged on 29 June 2022.

Table 3.

Laboratory analyses for a 1-year-old male who was initially admitted because of experiencing a pallid-yellow face for 1 week and pale red urine on one occasion more than 10 days before admission, but who after initial diagnosis and treatment for acute haemolytic anaemia was readmitted due to fever with a preadmission temperature of 39.8°C.

Parameter	Value	Normal range
White blood cell count, ×109/l	12.41	5.1–14.1
Neutrophil ratio, %	42	13–55
Lymphocyte ratio, %	51	33–77
Haemoglobin, g/l	102	107–141
Platelet count, ×109/l	271	190–524
C-reactive protein, mg/l	10.32	<9.99
Amyloid protein A, mg/l	151.99	<10
Erythrocyte sedimentation rate, mm/h	17	<10
Reticulocyte absolute value, ×109/l	87.2	24–84
Reticulocyte percentage, %	0.021	0.005–0.0015
Procalcitonin, ng/ml	0.127	0–0.046

On 7 July 2022, genetic screening was conducted on the child, revealing a heterozygous missense mutation in the ERCC4 gene. The mutation was inherited from the child's mother and was identified through screening nearly 700 genes for hereditary disorders of the blood and immune system. The mutation has not been reported in international databases of thousands of individuals and has a predicted damage score of 0.70. However, it is essential to note that the gene is inherited in an autosomal recessive manner, which means that it is not theoretically likely to cause morbidity.

On 21 February 2023, the child was admitted to the Department of Paediatric Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu Province, China for the third time due to a slightly red colour in his urine and a pallid face . Four days prior to admission, the child's family reported that the child had a blood test at a local hospital that showed a haemoglobin level of 106 g/l. However, the haemoglobin level dropped to 92 g/l and his temperature rose to 38.9 °C with a mild cough on the day of admission. During examination, the child was mildly anaemic with a congested pharynx and coarse breath sounds upon auscultation of both lungs. The reticulocyte percentage upon admission was 0.093% and the absolute reticulocyte count was 315.50 × 10⁹/l. Blood and urinary amylases were normal, while the chest radiograph did not reveal any significant abnormalities in the heart, lungs or diaphragm (Figure 1c). To find the cause of the haemolysis, the child's alveolar lavage fluid was collected and it stained positive for haemosiderin. Chest CT showed diffuse alveolar exudate in both lungs (Figure 1d). Furthermore, bone marrow aspiration suggested biphasic anaemia.

After undergoing several tests during his third hospitalization between 21 February 2023 and 2 March 2023, the child was diagnosed with idiopathic pulmonary haemosiderosis. The child was treated with 0.14 g Peramivir once a day by intravenous drip from 22 February 2023 to 24 February 2023; 0.35 g cefotiam every 8 h by intravenous drip from 24 February 2023 to 2 March 2023; 20 mg methylprednisolone once a day by intravenous drip from 25 February 2023 to 2 March 2023. Additionally, the child received nebulized inhalation of 2 mg budesonide suspension twice a day and continued to take the prescribed daily dose of methylprednisolone between 25 February 2023 and 2 March 2023.

The patient was followed-up after the final discharge. The child was prescribed 25 mg prednisone acetate orally once a day for 1 month. One month later, the child went to a Tan Chang County Traditional Chinese Medicine Hospital and their blood count showed the following: a leukocyte count of 19.78 × 10⁹/l; a neutrophil ratio of 0.67; a lymphocyte count of 0.25 × 10⁹/l; a red blood cell count of 5.04 × 10¹²/l; a haemoglobin level of 128 g/l; a platelet count of 355 × 10⁹/l.

Written informed consent was obtained from Lanzhou University Second Hospital, Lanzhou, Gansu Province, China to publish any potentially identifiable images or data in this case report. The patient's legal guardians/next of kin provided written informed consent for the publication of any potentially identifiable images or data in this article. The reporting of this study conforms to CARE guidelines. ⁴

Discussion

Idiopathic pulmonary haemosiderosis is a rare disease in children that presents with diffuse intrapulmonary haemorrhage. ¹ It is most often seen in children under 10, with a rate of about 0.24 cases per million children per year and there is no difference between the sexes.^5,6 Clinical presentation of this disease is non-specific and may include symptoms such as fever, fatigue and dyspnoea. The classical triad of haemoptysis, pulmonary infiltrates and iron deficiency anaemia may also be present, although in some cases, iron deficiency anaemia alone may be the only symptom.^2,7 This current case was unusual because the child only presented with haemolytic anaemia and a history of ingesting diesel.

Diagnosis of idiopathic pulmonary haemosiderosis is challenging as any condition that causes pulmonary haemorrhage can lead to haemosiderin deposition. The diagnosis is confirmed by ruling out other disorders that cause diffuse pulmonary haemorrhages, such as autoimmune diseases, infectious diseases and heart disease. Lung biopsy is the gold standard for diagnosis and is usually recommended for adults after excluding conditions such as capillaritis or vascular inflammation. ⁸ In infants and children, bronchoalveolar lavage staining is a simple and convenient method for detecting haemosiderin deposition and can aid in diagnosis. ⁹ The diagnosis of this disease is often delayed and can easily be misdiagnosed as anaemia or bronchopneumonia. In addition, because it is a rare disease poorly understood by clinicians, it may not be considered promptly.^10,11

Corticosteroids are the primary drug used to treat idiopathic pulmonary haemosiderosis. In addition, the long-term use of immunosuppressant drugs may be necessary to improve the prognosis of the disease.^9,10 Azathioprine, hydroxychloroquine and mycophenolate mofetil, among other steroid sparing agents, have been employed. A review of the paediatric idiopathic pulmonary haemosiderosis literature demonstrates that patients who have been administered corticosteroids and other immunosuppressants have experienced a considerable increase in their survival rate. ¹²

It is essential to consider the possibility of idiopathic pulmonary haemosiderosis in cases of recurrent pulmonary haemorrhage of unknown origin, as early diagnosis and treatment are crucial to reducing mortality. Delayed diagnosis can lead to hypoxia and worsened lung function, negatively impacting on the patient’s prognosis. Therefore, clinicians should remain aware of the possibility of idiopathic pulmonary hemosiderosis as a potential cause of pulmonary haemorrhage in children to ensure timely diagnosis and appropriate treatment. ¹³

In this current case, a male child was admitted to the hospital with haemolytic anaemia as their only apparent symptom. Despite several tests, the cause of the haemolysis remained unclear. During the second hospitalization, the haemoglobin level of the child had increased to 102 g/l, but during the third hospitalization, the haemoglobin level of the child had fallen to 96 g/l. This raised concerns amongst the physicians and prompted further investigations. Alveolar lavage fluid staining and a chest CT were performed, revealing the presence of haemosiderin deposits in the alveolar lavage fluid and diffuse alveolar exudate in both lungs. Based on these findings, a diagnosis of idiopathic pulmonary haemosiderosis was confirmed.

In conclusion, this current case report emphasizes the rarity of idiopathic pulmonary haemosiderosis and the importance of considering it as a possible diagnosis in children with recurrent anaemia of unknown cause. Prompt diagnosis can be achieved using alveolar lavage staining and high-resolution CT of the chest. Early diagnosis and treatment are crucial for improving the prognosis of this disease. Clinicians should keep idiopathic pulmonary haemosiderosis in mind when evaluating children with haemolytic anaemia and promptly initiate testing and treatment to prevent misdiagnosis and improve outcomes.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231210402 - Supplemental material for Idiopathic pulmonary haemosiderosis misdiagnosed as haemolytic anaemia: a case report

Supplemental material, sj-pdf-1-imr-10.1177_03000605231210402 for Idiopathic pulmonary haemosiderosis misdiagnosed as haemolytic anaemia: a case report by Xueqin Ma, Changxi Ju, Xiaotong Liu, Ying Tian, Jing Wu and Yuanxiao Li in Journal of International Medical Research