PATIENTS

Eleven patients (eight boys and three girls) presented to the Regional Respiratory Unit of the Royal Liverpool Children's Hospital at Alder Hey between 1986 and 1997. Median age at presentation was 5 months (range birth to 16 months). The diagnosis was made by typical clinical findings (such as dyspnoea and dry cough) in association with the radiological finding of diffuse interstitial infiltrate. The diagnosis was confirmed by histology on samples obtained by percutaneous lung biopsy5 in all but one case.

The patient hospital and general practice medical records were scrutinised for the time and nature of the first respiratory symptoms, the date of this first medical consultation, and the presenting complaint. Details of the pregnancy, perinatal history, family history, the age at which the child was referred to the Regional Respiratory Unit, and age of diagnosis were also noted.

INVESTIGATIONS

All patients underwent physical examination including assessment of growth and development, full blood count, blood electrolytes, liver function tests, and coagulation screen. Other investigations included immunoglobulins, viral serological, sweat test, autoantibodies, α₁ antitrypsin, lymphocyte CD4 to CD8 ratios, skin allergy testing, upper gastrointestinal contrast studies, radioisotope milk scans, and echocardiograms. Assessment of hypoxia included either random pulse oximetry oxygen saturation or overnight oxygen saturation studies. Patients old enough to comply had their respiratory function (peak flow (PEF), forced expiratory volume in one second (FEV₁), and forced vital capacity (FVC)) measured at least annually. Radiological investigations on all patients included standard anterior posterior chest radiographs; all images since 1995 have been taken with computer digital enhancement, and computerised tomography was performed under general anaesthesia. Bronchoscopy and bronchoalveolar lavage was carried out in one child using a well recognised protocol.6

PERCUTANEOUS LUNG BIOPSY

Histological samples of the lung were obtained by fluoroscopically guided percutaneous needle biopsy using the standard described technique.5 The procedure was performed while the patient was ventilated under general anaesthesia. The biopsy site selected was the lung area of maximum infiltration that was furthest from major vessels and any cystic areas identified on computed tomography (CT) scanning. Between one and two samples were taken on each occasion. No major complications occurred after the procedure. All patients remained well. The biopsy had to be repeated on one patient because of insufficient lung sample. One biopsy sample (patient 9) on further histological review was felt to unhelpful as it contained insufficient lung tissue.

HISTOLOGICAL ANALYSIS

All tissue samples were processed routinely for standard histological investigation (formalin fixed, paraffin embedded) and stained by the routine battery of staining methods including haematoxylin and eoxin, PAS, van Giesson, Masson Trichrome, and Prussian stain (for iron). In six cases touch imprints were made from the fresh tissue cores and stained by Giemsa and haematoxylin and eoxin method. Electron microscopic investigation was not performed in any of the cases. Immunohistochemistry (monoclonal antibody S100) was applied in only two cases (patients 2 and 5) in order to differentiate the mononuclear cells from the Langerhans cells in the chronic inflammatory infiltrate.

PATIENT CHARACTERISTICS

Table 1 gives patient details and table 2 treatment response. The median age of first respiratory symptoms was at birth (range: birth to 5 months). Six were symptomatic at birth with 10 of the 11 presenting at or before 3 months of age. The most common presenting sign was tachypnoea associated with rib indrawing, occurring in nine cases. Four had significant cough while only one patient had symptoms of wheeze at presentation. The median time between first onset of symptoms and referral to our department was 18 weeks (range: birth to 14 months). The median age of diagnosis was 9 months (range: 7 weeks to 4 years). The median time taken for the diagnosis to be confirmed by biopsy (in 10 of the 11 patients) after referral was four weeks (range: 1 week to 3 years). Patient 9 had the diagnosis of fibrosing alveolitis made on clinical and radiological grounds as the lung biopsy contained insufficient lung tissue. At presentation at 9 weeks of age, patient 4 had increased interstitial shadowing of both lungs on a chest radiograph. A CT scan performed on the same day was suggestive of pulmonary fibrosis which was confirmed by biopsy one week later. A significant delay between the referral and final diagnosis was seen in three patients (1, 2, and 8). This was because at presentation each had mild symptoms of bronchial reactivity and no evidence of hypoxia. Prior to referral for investigation, five of the 11 patients were thought to have recurrent lower respiratory tract infections. Patient 2 was thought to have tracheal stenosis. Patient 5 had right heart failure secondary to pulmonary hypertension and patient 7 was thought to have Wilson–Mikity syndrome. At the time of referral, seven of the 11 patients were failing to thrive, defined as a weight below the 10th centile.

PREGNANCY, PERINATAL, AND FAMILY HISTORY

Seven of the infants were born at term after a normal pregnancy. Five term infants experienced symptoms from birth, of whom two required oxygen in the first few days of life. Four patients were born preterm; three required oxygen in the first week of life. Patient 11 was one of twins. On antenatal scan at 20 weeks of gestation she was noted to have intrauterine growth retardation. The other twin was born at a normal weight and has been well throughout. There was no familial history of fibrosing alveolitis or lung fibrosis in any of the patients.

DIAGNOSIS AND INVESTIGATION

All patients in the study showed evidence of diffuse bilateral interstitial shadowing on chest radiographs. On CT scan in nine patients the interstitial fibrosis was widely disseminated throughout both lungs. Patient 1 had fibrosis that on first CT scan was located only in the right middle lobe, while patient 4 had bilateral fibrosis localised to the middle and lower regions of the lung. In patient 8, these changes evolved over a two year period. Evidence of bullae was noted on CT scan in three cases. Investigations were performed to exclude cystic fibrosis, viral respiratory infections, autoimmune disease, gastro-oesphagael reflux and aspiration, and immunodeficiency. Echocardiography where requested was normal in all cases apart from patients 5 and 10. Patient 5 presented with pulmonary hypertension and mild right ventricular heart failure that had resolved when subsequently investigated. Patient 10 was found to have a small and clinically insignificant foramen ovale. The bronchoalveolar lavage performed on patient 8 showed a cell count which was consistent with the histological diagnosis of fibrosing alveolitis (total cell count was raised and there was an increase in the percentage number of neutrophils2 ,7).

Respiratory function tests were performed in all children old enough to comply (see table 3). Restrictive pulmonary function was seen in all patients. There was no improvement in percent predicted lung function in the three year period between first and latest testing.

HISTOLOGY

All patients had a percutaneous lung biopsy performed. Patient 9 was excluded from the histological analysis as his biopsy sample did not contain sufficient lung tissue. All histological sections were reviewed by one pathologist (GK) and assessed for microscopic diagnostic features of idiopathic pulmonary fibrosis. These included:

• Lesions within alveolar septa such as oedema, fibrosis, elastic fibres

• The cellular contents of the alveolar septa: type 2 pneumocytes, lymphocytes, monocytes, fibroblasts, and polymorphonuclear cells

• The character of cellular content (lymphocytes, macrophages, polymorphonuclear cells) in alveolar lumina.

Table 4 summarises these findings.

Among a variety of lesions the most constant and striking histopathological changes were interstitial fibrosis, hyperplasia of type 2 pneumocytes, and interstitial inflammatory infiltrate. The intensity of the interstitial fibrosis was considerable in only two samples (patients 2 and 11), moderate in five, and mild in three. Hyperplasia of type 2 pneumocytes was considerable in one (patient 11), moderate in one, mild in six, and of only borderline intensity in two biopsy samples (patients 4 and 5). Chronic mononuclear interstitial inflammatory infiltrate consisting of lymphocytes and macrophages, was evident in all biopsy samples and showed mild to moderate range of intensity. The density of lymphocytes was moderate in two, mild in five, and virtually absent in three samples (patients 6, 7, and 11). In one of them, instead of lymphocytes numerous plasma cells were detected (patient 11). Macrophages were moderately numerous in one sample (patient 11) and mild in seven. In two samples no macrophages were seen (patients 3 and 5). Neutrophil granulocytes were only present in small numbers and detected in three biopsy samples (patients 2, 3, and 8). The amount of elastic fibres in the interstitium and alveolar septae was assessed as moderate in two (patients 2 and 11) and mild in eight tissue samples. In addition, the number of fibroblasts was considerably raised in only one (patient 11), moderately in four, and slightly in five lung samples. The intra-alveolar cell population consisted predominantly of macrophages. They were identified in small numbers in most of the samples. The macrophage number was high in one sample (patient 11), giving the appearance of a desquamative interstitial pneumonia. In addition the cytoplasm was loaded by iron (focal secondary haemosiderosis). Lymphocytes were rarely seen and detected only in small numbers in two samples (patients 2 and 11). Neutrophilic granulocytes were absent from alveolar spaces in all biopsy samples.

TREATMENT

All patients received an initial course of prednisolone 2 mg/kg for three months. A steroid response was noted in six patients. If there was no clinical response, then the steroids were withdrawn. Where a steroid response was seen, prednisolone was continued at 1–1.5 mg/kg daily for one month before changing to alternate day treatment. The average length of a continued course of steroids was two years and five months (median one year and three months; range four months to six years and three months). In two infants side effects were noted. One infant had abdominal pain after which the steroids were withdrawn. Patient 5 had some Cushingoid features noted at 2 years of age after which his steroid dose was reduced. Patient 11 has continued to deteriorate despite oral prednisolone. Her steroids were stopped and treatment was changed to hydroxychloroquine with a good response. Six patients had reversible bronchial reactivity and responded to inhaled steroids and bronchodilators.

A dietitian assessed nutrition in every patient. Seven were failing to thrive and received high energy diet supplementation. Weight gain was maintained in all cases. Five grew parallel to their presenting weight centile. Only patient 6 was able to regain his original birth centile.

Five patients required home oxygen. Patients 7 and 9 have been successfully weaned into air. Patients 10 and 11 have been weaned to flow rates between 1 and 0.5 litres per minute while patient 5 needs nocturnal oxygen only.

All 11 patients are alive at a median age of 6 years since the diagnosis was made (range: 1 month to 10 years). Two patients are without symptoms. A further six infants have experienced dyspnoea with moderate activity. The remaining three affected children still require oxygen.