Diffuse Alveolar Hemorrhage: A Rare Underlying Disease in a Child with Chronic Respiratory Symptoms

Rajesh Kulkarni; Rhea Singh; Himanshu Gohatre; Arvind Kumar

doi:10.4103/ipcares.ipcares_3_23

CASE REPORT

Year : 2023 | Volume : 3 | Issue : 2 | Page : 96-101

Diffuse Alveolar Hemorrhage: A Rare Underlying Disease in a Child with Chronic Respiratory Symptoms

Rajesh Kulkarni¹, Rhea Singh¹, Himanshu Gohatre¹, Arvind Kumar²
¹ Department of Pediatrics, PCMC's Post Graduate Institute YCM Hospital, Pune, Maharashtra, India
² Department of Pediatrics, Armed Forces Medical College, Pune, Maharashtra, India

Date of Submission	02-Jan-2023
Date of Decision	11-Apr-2023
Date of Acceptance	13-Apr-2023
Date of Web Publication	24-May-2023

Correspondence Address:
Dr. Rajesh Kulkarni
Department of Pediatrics, PCMC'S Post Graduate Institute YCM Hospital, Pune, Maharashtra
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_3_23

Abstract

Background: Diffuse lung disease (DLD), conventionally known as interstitial lung disease (ILD), encompasses a spectrum of diseases involving the pulmonary parenchyma with impairment of gaseous exchange. Most of the diseases under DLD have similar presentations, but appropriate investigations can delineate the exact disease. Diffuse alveolar hemorrhage (DAH) is one of the diseases under this umbrella group of DLD. Clinical Description: A 3-year-old girl suffering from persistent breathlessness and intermittent hypoxic exacerbations over 1 year, presented to us with acute respiratory worsening. She was underweight with stunting and had severe pallor. She had received blood transfusions in previous hospitalizations. Chest-X-ray shows reticular opacities, with High Resolution Computed Tomography (HRCT) chest showing bilateral diffuse ground glass opacities involving all lobes with the prominent pulmonary artery. The broncho-alveolar lavage showed hemosiderin-laden macrophages, thereby confirming alveolar hemorrhage. Antinuclear antibody was positive, though double-stranded DNA and Anti-neutrophil cytoplasmic antibody were negative. The child was thus diagnosed with a case of DAH, probably, immune mediated. Management: The child was treated with supportive care, including oxygen, intravenous fluids, antibiotics, and packed red cell transfusion. Even after improvement in hemoglobin, oxygen dependency persisted. The child was then administered Intravenous Immunoglobulin and prednisolone, to which the child showed a response with gradual weaning off oxygen. Conclusions: In any child presenting with persistent respiratory symptoms, especially exercise intolerance, over a prolonged period with intermittent hypoxic exacerbations, a pediatrician should consider diagnoses beyond infections and multitrigger wheezing. Such manifestations, particularly if associated with failure to thrive, may be due to DLD. DAH, a rare form of DLD, may be a possibility in such children.

Keywords: Diffuse lung disease, hemosiderin-laden macrophage, idiopathic pulmonary hemosiderosis, immune mediated, interstitial lung disease

How to cite this article:
Kulkarni R, Singh R, Gohatre H, Kumar A. Diffuse Alveolar Hemorrhage: A Rare Underlying Disease in a Child with Chronic Respiratory Symptoms. Indian Pediatr Case Rep 2023;3:96-101

How to cite this URL:
Kulkarni R, Singh R, Gohatre H, Kumar A. Diffuse Alveolar Hemorrhage: A Rare Underlying Disease in a Child with Chronic Respiratory Symptoms. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Jun 6];3:96-101. Available from: http://www.ipcares.org/text.asp?2023/3/2/96/377520

A child with chronic respiratory symptoms, in the form of exercise intolerance with intermittent hypoxic exacerbations, associated with failure to thrive, may be harboring an underlying diffuse lung disease (DLD), conventionally known as interstitial lung disease (ILD), which encompasses a wide range of disorders involving the pulmonary parenchyma impairing gas exchange. After common causes are excluded, a child with unexplained pulmonary symptoms and diffuse pulmonary infiltrates should be given a provisional diagnosis of DLD, and further specific investigations are to be done to reveal the underlying etiology.^[1] We describe a child with diffuse alveolar hemorrhage (DAH), suffering from persistent breathing difficulty, who remained undiagnosed for nearly a year.

Clinical Description

A 3-year-old, completely immunized, developmentally normal girl, born of the nonconsanguineous marriage, was admitted to our hospital with complaints of moderate fever for 2 days with labored breathing and cough since 1 day. There was a history of decreased appetite, and parents noted that the child was appearing pale since a week before the current admission. The child had been suffering from persistent fast breathing with exacerbations over the last 1 year. There was a history of persistent cough for 1 year with no specific aggravating relieving or exacerbating factors. There was no history of cold, nasal or ear discharge, vomiting, hemoptysis, or hematemesis. There was no associated rash, oral ulcers, joint pain or atopy and no history of recurrent skin or bowel disturbances, and no abnormal consistency of stool. There was no contact with a person suffering from tuberculosis, nor any sustained exposure to birds or organic dust. She was born at term by normal delivery at a hospital with a birthweight of 2.5 kg. The antenatal, natal, and postnatal periods were uneventful. She had been exclusively breastfed until 6 months of age, and later, appropriate complementary feeds were given.

The child was apparently well till a year before presenting to us. She had been hospitalized three times in the past year. In the first instance, she was admitted to the pediatric intensive care unit with 1-week history of fever and breathlessness. She was found to have severe anemia (hemoglobin 2.5 g/dl), with mean corpuscular volume 62 fl, mean corpuscular hemoglobin 21 pg, total leukocyte count of 8800/cmm, platelets 248000/cmm. Her anemia workup showed a peripheral smear suggestive of microcytic hypochromic anemia, and a negative Direct Coomb's test (DCT). Other investigations during this hospital admission showed a negative blood culture, COVID RT-PCR negative, and chest X-ray showing bilateral infiltrates. A 2 D echo was done, suggestive of moderate pulmonary hypertension (pulmonary artery systolic pressure 60 mmHg) with moderate tricuspid regurgitation. She was treated with intravenous antibiotics and received two packed red cell transfusions for anemia during her hospital stay. The child was oxygen dependent till discharge so she was discharged on home oxygen supplementation with oral furosemide and spironolactone after 2 weeks of hospital stay. She was diagnosed with bronchopneumonia with pulmonary hypertension.

She required two further hospitalizations, 4 months apart, again for fever and breathlessness, with persistent oxygen requirement present in between the episodes. She required packed red cell transfusions during both hospitalizations for anemia (hemoglobin was documented to be 4 g/dl on both occasions). The blood cell indices of the child during the four instances of hospitalizations are shown in [Table 1].

Table 1: Blood cell indices of the child in the four instances of hospitalization

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In the current hospitalization, the child was found to be febrile and dyspneic with severe pallor. The anthropometric evaluation revealed a weight of 10 kg (weight for age at Z score: −3), the height of 87 cm (height for age Z score: −2), with weight for height Z score: −1 and mid-upper arm circumference 14 cm, which indicated that the child was stunted and underweight. The occipito-frontal circumference was 47 cm (at the 5^th centile). She had a heart rate of 112/min, respiratory rate of 46/min on room air, improving to 30/min on oxygen, blood pressure of 86/56 mmHg, with normal volume pulses, and normal capillary refill time. Oxygen saturation (SpO₂) was 78% on room air, which improved to 97% on oxygen support using nasal prongs (2 L/min). The child had severe pallor, but there was no cyanosis, clubbing, icterus, or lymphadenopathy. There was no edema. Respiratory system examination revealed chest in drawing with substernal retractions while auscultation revealed basal crepitations audible suggestive of congestive heart failure (CHF). There was no clinical evidence of pulmonary hypertension in the form of a loud second heart sound or diastolic shock. There was mild tender hepatomegaly (2 cm palpable liver with liver span 6 cm). Central nervous system examinations were normal.

Investigations revealed hemoglobin of 4.4 g/dL, MCV 58 fl, MCH 20 pg, leukocytosis (14,000/uL) with normal platelet count (4.5 lakhs/mm³). The peripheral smear was suggestive of microcytic hypochromic anemia. Serum bilirubin levels in total and direct components were 0.8 mg/dl and 0.4 mg/dl, respectively. Alanine transaminase and aspartate transaminase levels were 24 U/L and 34 U/L, respectively. DCT was negative; reticulocyte count was elevated (5%), and serum LDH was high (460 U/L). Workup for fever revealed normal results of rapid malaria test, blood culture, urine routine, and culture. C-reactive protein was mildly elevated at 12 mg. dl, and ESR was 48 mm at 1 h. The chest radiograph showed a bilateral reticular pattern [Figure 1]. High-resolution computerized tomography (HRCT) of the chest revealed features of bilateral diffuse ground glass opacities involving all lobes with prominent pulmonary arteries [Figure 2]. Echocardiogram showed a structurally normal heart with normal biventricular function and moderate pulmonary hypertension (50 mmHg). Workup for the causes of DLD, including investigations for tuberculosis (Gastric lavage for GeneXpert, AFB, and Tuberculin test) and HIV enzyme-linked immunosorbent assay were negative. The sweat chloride level was 21 mmol/L, ruling out cystic fibrosis. Complement levels were wihin normal limit, urine protein/creatinine ratio was 0.05. Anti-nuclear antibody (ANA) by immunofluorescence with dilution 1:80 with intensity 3+ with the homogeneous pattern was strongly positive, while anti-neutrophil cytoplasmic antibody (ANCA) and double-stranded DNA (dsDNA) were negative. Bronchoscopy was done and the broncho-alveolar lavage (BAL) showed hemosiderin-laden macrophages (HLMs) suggestive of alveolar hemorrhage [Figure 3]. We could not do lung biopsy and genetic studies due to a lack of feasibility.

Figure 1: Chest X-ray showing bilateral reticular shadows

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Figure 2: HRCT showing extensive diffuse ground glass haziness in the bilateral lung parenchyma with areas of consolidation, predominantly in the perihilar region in the right upper, middle, and lower lobe. HRCT: Hgh resolusion computed tomography

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Figure 3: BAL showing hemosiderin laden macrophages. Arrows are showing hemosiderin laden macrophages. BAL: Broncho-alveolar lavage

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The child was initially provided oxygen via nasal prongs oxygen (2 L/min), with maintenance intravenous fluids, intravenous antibiotics (Cefotaxim and Amikacin), pure red cell transfusion with furosemide. The history, clinical and radiological features suggested a diagnosis of immune-mediated DAH. Thus, further treatment was given with Intravenous Immunoglobulin (IVIG) at 2 g/kg, and later, oral prednisolone was started at a dose of 2 mg/kg. The child responded well to the treatment, and her respiratory rate and breathing difficulty gradually decreased. Four days after giving IVIG and prednisolone child started maintaining SpO₂ off oxygen as well. The child was discharged after 12 days of hospitalization without oxygen support. At follow-up after 4 weeks, she had continued to do well with no breathlessness in between and had saturation of 97% on room air. The chest X-ray at follow-up showed relative clearance of the reticular shadows [Figure 4].

Figure 4: Chest-X-ray after treatment showing the clearing of reticular shadows

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Discussion

The constellation of features in the case described above, including persistent respiratory distress, with long-term oxygen requirement, with mild pulmonary hypertension on echocardiography, with recurrent episodes of fall in hemoglobin requiring multiple blood transfusions, ANA positivity and presence of HLMs, responding to IVIG and steroids, was consistent with a diagnosis of immune-mediated diffuse alveolar hemorrhage.

DAH is a rare disease in children, the incidence of the different etiologies of DAH is largely unknown in the pediatric population.^[2] The condition is one of the diseases in the spectrum of diseases listed under DLD. The term DLD reflects the spectrum of underlying pathology, which often includes extensive alteration of alveolar and airway architecture, in addition to changes in the interstitial compartment. These disorders have traditionally been described as “interstitial lung disease” (ILD), but that term is less accurate because the interstitium is not involved in some types.^[3],[4]

In DAH, the bleeding most commonly originates from the low-pressure pulmonary microvasculature as a result of microvascular damage resulting in blood leakage into the alveolar spaces.^[5],[6] A variety of diseases may be associated with the development of the DAH. As per current classification schemes [Table 2], DAH is divided into two broad categories: immune mediated and nonimmune mediated with immune-mediated hemorrhage being more common. The most common causes of immune-mediated DAH are the ANCA-associated vasculitides (AAV) and idiopathic pulmonary capillaritis. The most common AAV in the pediatric age is granulomatosis with polyangiitis which has an estimated incidence of 0.64/100,000/year.^[7] Nonimmune disorders, which may be of cardiac or noncardiac origin, or idiopathic disorders.^[2] In children, the most frequent nonimmune causes of DAH are infections and cardiovascular diseases.^[8] The classic triad of symptoms includes hemoptysis, anemia, and diffuse pulmonary infiltrates.^[2] Although hemoptysis is the usual presenting symptom, it is not always seen in children who may not expectorate.^[9],[10]

Table 2: Classification of diffuse alveolar hemorrhage^[5]

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Children can present acutely with respiratory failure or more indolently with a long duration of chronic symptoms, including tachypnea, retractions, cough, persistent unexplained hypoxemia, exercise intolerance, failure to thrive, or other nonspecific symptoms. While the case described by us did not have hemoptysis, the child had a prolonged course with recurrent exacerbations of respiratory distress associated with fall in hemoglobin.^[11],[12] Fullmer et al. described eight children with the median age of 8 years diagnosed with pulmonary alveolar hemorrhage due to pulmonary capillaritis. They presented with the clinical manifestations of cough, hemoptysis, hypoxia, and hemoptysis. While hypoxia was seen in 6/8 children (75%), hemoptysis was seen in only 25%.^[13] Diffuse alveolar hemorrhage has also been reported in infants, by Gkogkou et al., where the five infants ranged from the age of 3 and 18-week-old, all of whom presented with hemoptysis, dyspnea, anemia and abnormal chest X-rays, diagnosed by bronchoscopy.^[14]

Historically, many of the cases of DAH have been diagnosed with idiopathic pulmonary hemosiderosis (IPH), characterized by diffuse infiltrates, anemia, and alveolar HLMs. The pathogenesis of IPH is unclear, with PH being a diagnosis of exclusion; various causes like allergic (as in cow's milk hypersensitivity or Heiner syndrome), environmental, genetic, and autoimmune have been proposed.^[10] The national network database from 12 French pediatric respiratory centers, identified 25 cases of IPH in children, with a median age of 4.3 years presenting with dyspnea (68%), anemia (64%), cough (48%), febrile pneumonia (44%), and hemoptysis (44%). They were diagnosed by BAL showing the presence of HLMs, or by lung biopsy. The immunological profile revealed positive ANCA (40%), ANA (45%), and specific coeliac disease antibodies (28%).^[10] In our case, ANA was positive, while dsDNA and ANCA were negative and there were no other symptoms suggestive of lupus or systemic vasculitis.

Regardless of the etiology, children with DAH present with anemia and diffuse infiltrates in chest X-ray. Chest CT scan usually shows diffuse ground glass opacities and septal thickening or nodules. Bronchoscopy confirms hemoptysis and also delineates the site of bleeding. Grossly hemorrhagic BAL fluid, with increasing blood content in successive aspirations, is diagnostic of acute alveolar hemorrhage, and the demonstration of HLMs is diagnostic of sub-acute alveolar hemorrhage, as hemoglobin is converted to hemosiderin by alveolar macrophages.^[2] The clinical presentation in our case was consistent with that of DLD, but the child was misdiagnosed with persistent pneumonia for 1 year before admission to our hospital. The investigations such as chest CT and bronchoscopic examination with BAL showing HLMs confirmed the diagnosis. A lung biopsy may be done in a patient with diffuse hemorrhage and negative ANCA to help distinguish between immune and nonimmune-mediated hemorrhage. However, as the diagnosis of DAH can be made by less invasive procedures, lung biopsy is not always justified. In our case, lung biopsy was not logistically feasible.

In milk-fed infants, investigations for antibodies to cow's milk proteins and milk-specific IgE are to be considered. Evaluation for coagulation disorders, screening for a cardiac etiology as well as specific serologic testing for ANA and its components, anti-glomerular basement membrane antibodies, and ANCAs to detect immune-mediated lung disease.^[2],[12]

Immune-mediated hemorrhage requires more aggressive immunosuppressive therapy, compared to those with nonimmune DAH. After a median follow-up of 5.5 years, in the French cohort,^[10] satisfactory outcome was seen in 23/25 children. Our child responded well to IVIG and prednisolone and was able to get weaned off oxygen. After a short follow-up period of 4 weeks, she was found to be asymptomatic.

Conclusion

Although DLD is a rare entity, it must be considered in any child suffering from persistent tachypnea with labored breathing over a prolonged period, having intermittent hypoxic exacerbations, especially when associated with failure to thrive. Diffuse alveolar hemorrhage is one disease leading to DLD, and appropriate investigations can delineate this ethology.

Declaration of patient consent

The authors certify that they have obtained the appropriate consent from the parents. In the form, the patient's parents have given his consent for the images and other clinical information to be reported in the journal. The patient's parents understand that the name and initials will not be published, and due efforts have been made to conceal the same, but anonymity cannot be guaranteed.

Acknowledgment

We acknowledge the help from the Department of Pathology Armed Forces Medical College and Rheumatologist, Command Hospital, Pune.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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