A 40 year-old African American male presents to The Johns Hopkins Hospital for evaluation of shortness of breath, night sweats, fevers, weight loss, and a cough productive of yellow sputum.

The patient is a 40 year-old male who presented to an outside institution with splenomegaly, hepatomegaly, and paraaortic lymphadenopathy one year prior to admission. Hematologic evaluation at that time revealed pancytopenia with abnormally increased monocytes. A bone marrow biopsy was performed, which demonstrated a hypercellular and fibrotic bone marrow. Due to his myelofibrosis, the patient was started on hydroxyurea and iron. A splenectomy was also performed at that time, which revealed congestion and extramedullary hematopoiesis.

Five months prior to admission, the patient experienced fluctuating bilateral lower extremity edema, worsening night sweats, weight loss, and a nightly cough. Evaluation at an outside institution revealed bilateral basilar pulmonary effusions and infiltrates on chest radiograph. Laboratory evaluation revealed elevated lactate dehydrogenase (900 U/L), elevated alkaline phosphatase, decreased albumin (3.1 grams per deciliter), macrocytic anemia, Howell-Jolly bodies, anisocytosis, and elevated bands and metamyelocytes. He continued hydroxyurea. The patient was awaiting bone marrow transplant at this time with a working diagnosis of chronic myelomonocytic leukemia (CMML).

He presented to The Johns Hopkins Hospital with shortness of breath, night sweats, weight loss, a cough productive of yellow sputum and watery diarrhea. These symptoms had been present for at least 3-4 weeks. He had minimal shortness of breath at rest, but marked cough and dyspnea on exertion. The patient reported he could climb 1 but not 2 flights of stairs. He reports daily night sweats with feeling 'feverish', however he had not measured his temperature. There was no chest pain or hemoptysis. He did have possible palpitations with exertion, but not at rest. He denied abdominal pain but did have anorexia and occasional watery stools. Over the past month he'd lost 5- 10 pounds.

The patient had no prior history of respiratory disease including asthma, pneumonia, bronchitis, or pneumothorax. He smoked 1 ppd for 20 years but quit when he considered bone marrow transplant. There was no history of illicit drug abuse or HIV risk factors. He'd traveled to Europe as a tourist and lived in surburban Baltimore County. He does not recall PPD testing and denies TB contacts.

CMML diagnosed prior to admission
No prior past medical history

Splenectomy

The patient's father had a history of multiple myeloma, diagnosed at age 59 years. No additional contributory history is provided.

The patient works at a toxic waste disposal company. He has lived in Illinois for the past 20 years but was transferred to Maryland about 9 months ago. He is exposed to unknown chemicals but generally wears respiratory protection when near chemicals. He has been unable to work for the past month. He lives with his wife and 3 children (ages 6-16). They have a cat and two parakeets (all healthy). His hobbies include bowling and fishing.

Hydroxyurea
Iron

No known drug allergies.

The patient notes night sweats and weight loss occurring for 1-2 months prior to admission.
No history of angina, MI, syncope, neurologic changes, biliary/pancreatic disease, renal dysfunction, joint abnormalities, or skin disease.
Cardiovascular risks include smoking only.

General: ill appearing thin male in no acute distress
Vital signs: Blood pressure 115/65 mmHg, Heart rate 105/min, Resp rate 18/min, SaO2 94% at rest, Temp 38.5 C
HEENT: no oral or eye lesions, nasopharynx normal, eyes normal. Temporal wasting.
Neck: supple
Cardiac: PMI normally located. Tachycardia with 2/6 systolic murmur at left sternal border and at apex. The JVP is flat but V-waves are visualized.
Chest: Bilateral lower crackles. SaO2 falls to 87% on room air climbing one flight of stairs.
Abdomen: Nontender, normal bowel sounds no palpable masses. Clean splenectomy scar. Stool heme negative
Extremities: 1+ pedal edema bilaterally
Skin: No rash.
Neuro: alert and oriented, mild diffuse distal weakness but symmetric examination. No proximal weakness, sensory or motor deficits. Cranial nerves normal.

Sodium 135, Potassium 4.0, Chloride 104, CO2 22, Blood Urea-Nitrogen 15, Glucose 106, Serum Creatinine 1.0, Calcium 7.9, Total Protein 7.6, Albumin 2.8, Total Bilirubin 3.3 Alanine Amino Transferase 24, Aspartate Amino Transferase 48, Alkaline Phosphatase 233 (30 - 120).

White blood cell count 10,183 (30% Neutrophils, 33% Lymphocytes, 37% Monocytes), Hemoglobin 8.5, Packed cell volume 27.8 %, Mean corpuscular volume 107.3, Platelet count 71, nucleated RBC number 1527, Nucleated red blood cells 15%. Direct Coombs negative; Vitamin B12 107; Fibrinogen 422; D-dimer 4.06; Serum lactic dehydrogenase 742; Haptoglobin < 6.

Peripheral blood smear: Moderate macrocytosis, marked anisocytosis, marked polychromasia, bizarre forms are seen; compatible with macrocytic, hypochromic anemia with dysplastic erythroid precursors; monocytosis and atypical lymphocytes; thrombocytopenia with some large forms suggestive of chronic myeloproliferative disorder

Urinalysis: normal

Sputum: gram stain with moderate number of white blood cells and gram negative bacilli, culture grew respiratory flora.

Stool: no WBCs

The patient was admitted to The Johns Hopkins Hospital with dyspnea, oxygen desaturation with exercise, productive cough, and bilateral ground glass opacities of the lungs on CT scan (Image 1). Bronchoscophy with bronchoalveolar lavage (BAL) was negative for infectious organisms. Cultures for bacteria, mycobacteria, and fungi remained negative over the course of hospitalization. During the following week, the patient developed daily, spiking fevers and increasing pulmonary infiltrates, which were unresponsive to broad-spectrum antibiotic administration (cefepime, vancomycin, metronidazole, azithromycin and voriconazole). Blood cultures were negative. The patients persistent anemia and thrombocytopenia required multiple transfusions of packed red blood cells and platelets. He remained tachycardic with low normal blood pressure. Intravenous fluids were administered. Over days, he developed signs of volume overload with elevated JVP and worsening lower extremity edema.

A repeat bone marrow biopsy demonstrated a markedly hypercellular marrow (90-95%) with increased reticulin fibrosis, but normal hematopoietic elements with normal maturation. Blasts were not increased. A plasmacytosis was present (10% of the cellularity), although kappa and lambda immunostains demonstrated polyclonality. The marrow findings supported a primary marrow disorder, although the differential diagnosis included a myelodysplastic syndrome, myeloproliferative disorder, or a combined myelodysplastic-myeloproliferative disorder.

Ten days after admission, the patient developed worsening respiratory failure requiring intubation and was transferred to the Medical Intensive Care Unit. Repeat bronchoscopy with BAL was performed. Broad spectrum antibiotics (as above) were continued. During the next 2.5 weeks, he developed progressive lactic acidosis, renal failure, increasing pulmonary pulmonary infiltrates, and increasing hypoxemia. Four weeks following admission, he developed refractory hypotension unresponsive to vasopressor therapy. After discussion with family, no further attempts at resuscitation were performed. The patient expired from cardiopulmonary failure.

Image 1: CT scan on admission, showing diffuse ground-glass densities

Images 2 and 3: Chest X-ray and CT scans two weeks into hospitalization, showing diffuse ground-glass densities with possible lymphadenopathy in hilum and mediastinum plus patchy, irregular perivascular interstital thickening, especially in left upper lobe

Image 4: CT scan four weeks into hospitalization showing consolidative pattern in both lungs with bilateral pleural effusions and increasing interstitial thickening

What is the most likely cause of the patients respiratory failure and death?