A 4-year-old female presented to the Pediatric Emergency Department at Royal University Hospital in Saskatoon, SK, Canada, with 4 days of worsening cough and increased work of breathing and one day of anuria. Her initial vital signs showed a temperature of 37.5 degrees Celsius, pulse rate of 125 beats per minutes, blood pressure of 114/58 mmHg, respiratory rate of 70 breaths per minute, and oxygen saturation of 95% on 30 litres of high flow oxygen with 21% FiO2. On exam, she had bilateral periorbital edema, crusted nasal discharge, and pallor. Rash and purpura were absent. She had nasal flaring, intercostal retractions, and coarse crackles bilaterally although more prominent on the right.
She had cough, sore throat, and rhinorrhea at a walk-in clinic approximately one-week prior and was given a prescription for amoxicillin. She also had iron deficiency anemia six months prior and started oral iron supplementation. She otherwise had no significant past medical history, significant travel history, or recent infectious contacts. Her mother, however, did have a history of treated tuberculosis (TB). Her immunizations were up to date.
Initial laboratory investigations revealed white blood cell count 9.08 x 109/L, decreased hemoglobin 60 g/L, and normal platelet count of 349 x 109/L. Her urea (16.9 mmol/L) and creatinine (46 umol/L) were elevated. She had a slightly elevated CRP (34.5 mg/L), normal glucose (6.7 mmol/L), normal sodium (142 mmol/L), high potassium (5.9 mmol/L), mildly elevated chloride (112 mmol/L), and a low bicarbonate (15 mmol/L). Her D-dimer was 929 ug/L, APTT was low-normal (22 seconds), and fibrinogen was normal (3.42 g/L). Her urinalysis demonstrated leukocyte esterase 500 WBC/uL, protein 1.5 g/L, and blood 250 RBC/uL, with negative nitrites. Urine microscopy revealed leukocytes 20-50 WBC/HPF, erythrocytes 11-20 RBC/HPF, and granular casts 3-5/LPF.
She was transferred to the Pediatric Intensive Care Unit (PICU) after over 250 mL of hemoptysis. Her initial arterial gas showed a normal anion gap metabolic acidosis with concomitant respiratory acidosis (pH 7.25, carbon dioxide 43 mmHg, bicarbonate 18 mmol/L, and corrected anion gap 13.5). Her first chest X-ray showed bilateral consolidations with air bronchograms, consistent with diffuse pulmonary hemorrhage (Figure 1). She was initiated on bilevel positive airway pressure, but she continued to deteriorate with worsening respiratory acidosis (arterial pH 7.01, carbon dioxide 73 mmHg, and bicarbonate 18 mmol/L). She was intubated and shortly thereafter required high frequency oscillation ventilation (HFOV).
With our suspected diffuse alveolar hemorrhage, an upper gastrointestinal bleed (GI) was considered in the differential diagnosis. We elected not to pursue investigations of the GI tract, because her initial management in the PICU after intubation was revealing. A nasogastric tube was promptly inserted which did not indicate any evidence of gastric blood. More importantly, initial tracheal aspirates from closed inline suctioning revealed bright red blood, with subsequent aspirates suggesting a mixture of bright red and congealed blood. With her microcuffed endotracheal tube inflated and routinely monitored (q12 hrs) for minimum inflation pressures, risks for significant aspiration should have been mitigated.
She received two transfusions of packed red blood cells to correct the anemia. Given her worsening clinical status and anuria, CRRT was initiated. This led to a rapid improvement in her electrolyte abnormalities. Further investigations revealed positive perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) with anti-myeloperoxidase antibody IgG 30, and negative cytoplasmic ANCA (c-ANCA) anti-proteinase 3 antibody IgG 2. Both complements C3 (0.18 g/L) and C4 (0.10 g/L) were low. Anti-glomerular basement membrane (GBM), anti-phospholipid, and antinuclear antibodies were negative.
Although vasculitis was strongly suspected due to the constellation of pulmonary and renal findings, infectious causes were also considered. Nasopharyngeal swab for rhinovirus was positive. Blood, urine, and lower respiratory cultures were negative. Mycobacterium tuberculosis polymerase chain reaction (PCR), acid fast bacilli stain, Bordetella, Mycoplasma pneumoniae, and Hantavirus PCR were also negative.
A renal biopsy was performed which demonstrated enlarged glomeruli with diffuse endocapillary hypercellularity with numerous neutrophils and closure of glomerular capillaries (Figure 2). There was endothelial cell swelling but no areas of glomerular capillary wall necrosis or cellular crescents. On immunofluorescent histology, C3 stain showed glomeruli with finely granular 3+, irregular diffuse staining of capillary walls, and mesangium (Starry sky pattern) and IgG demonstrated 1-2+ focal segmental, granular capillary wall staining. There was no immunopositivity with IgA antibody. Electron microscopy confirmed the increased numbers of endocapillary and infiltrative inflammatory cells in the glomerular tuft as well as swelling of endothelial cells. Scattered mesangial, subendothelial deposits were present. However, the classical subepithelial "hump like" deposits were rare. The case was also reviewed by pediatric nephropathologist to confirm the diagnosis of PIGN and to rule out C3 nephropathy. Following the biopsy, a streptozyme test was done which was positive with a titre of 1 : 100.
High dose methylprednisolone therapy was initiated under the suspicion of vasculitis following renal biopsy. Upon receiving the results of the biopsy 3 days after admission, corticosteroid was stopped and emphasis was given to supportive treatment. Her chest X-ray improved greatly by day 5 in hospital (Figure 3) and she was successfully weaned off HFOV and CRRT. She subsequently developed systemic hypertension, which was managed with captopril and amlodipine. At the age of 4 years she was too young for pulmonary function tests at our institution, and a CT chest did not seem warranted given her clinical improvement.
She was evaluated in pulmonary and nephrology follow-up clinics 3 months after discharge. There was no further history of cough, shortness of breath, or anemia and the CXR completely cleared. Her C3 and C4 normalized and her blood pressure remained normotensive. She will receive long-term monitoring for respiratory and renal impairment, but she is expected to have a complete recovery.