A 23-year-old man presented in March of 2014 to a community hospital in Maryland with four days of fever, chills, severe malaise, and myalgias, which he reportedly attributed to overexertion on a recent five-day ski trip to Vermont. Chest x-ray was unremarkable (Fig. 1a). He was given a diagnosis of viral upper respiratory infection and dehydration, and discharged from the Emergency Department in haste, as he needed to 'catch a flight to Hawaii' per hospital documentation. However, he returned later that day with severe dyspnea. Vital signs included maximum temperature to 102.7  Fahrenheit, heart rate 131 beats per minute, respiratory rate 48 breaths per minute, blood pressure 94/40, and arterial oxygen saturation was 55% on 100% oxygen via nasal cannula. He was emergently endotracheally intubated and copious bloody secretions from the endotracheal tube were noted. Other abnormalities included mild elevation of transaminases and total bilirubin, acute kidney injury (serum creatinine 2.3 mg/dL with protein and blood on urinalysis), rhabdomyolysis (creatinine kinase 2811 U/L), abnormal coagulation profile (prothrombin time 16.9 s, partial thromboplastin time 29 s, international normalized ratio 1.4), leukocytosis (18.3 K/l), anemia (hemoglobin 7.0 g/dL), and thrombocytopenia (96 K/ mul). CXR showed development of interstitial opacities (Fig. 1b). Vancomycin, ceftriaxone, azithromycin, and oseltamivir were initiated empirically at the community hospital, to cover for usual bacterial pathogens associated with community-acquired pneumonia including methicillin-resistant Staphylococcus aureus (MRSA), and influenza.
Within 12 h of intubation, the patient had decompensated further and had evidence of acute respiratory distress syndrome (ARDS) with Pa02/Fi02 of 62, bilateral infiltrates on chest x-ray, and no evidence of left atrial hypertension. The patient was transported by helicopter to a tertiary hospital critical care resuscitation unit, and immediately initiated on veno-venous ECMO and ventilated with a protective lung strategy. Bronchoscopy revealed severe erythema and inflammation of mucosa with increasing blood secretions returned with each bronchoalveolar lavage. Additionally he required vasopressors for severe acidosis and hypotension, and was initiated on continuous renal replacement therapy for oliguric renal failure. Twelve units of packed-red blood cells were infused in the first 24 h to maintain hemoglobin levels above 7.0 g/dL.
Infectious Diseases service and several other consult services were immediately notified of his arrival. On physical examination, the patient was critically ill appearing, sedated and ventilated with ECMO cannulas, endotracheal tube, and other support structures in place, but appeared to be a previously healthy well-nourished and well-developed young man. Crackles were heard in all lung fields. Rash, jaundice, and conjunctival injection were absent.
A thorough investigation into the patient's medical, social, and travel history revealed that he was on a scheduled break from active military service for the United States Navy; he serves on a submarine stationed in Pearl Harbor, Hawaii (HI). Past medical history was notable only for Bells palsy as a child due to Lyme disease, and he had received recommended childhood vaccinations. He had flown to Maryland from HI, and then driven to Vermont with a friend to ski and they had skied 'hard' for five days. They stayed in a cabin, which according to the friend was clean and otherwise unremarkable. Contact with medical personnel and military officials from his unit provided an accurate travel history for the antecedent 6 months of military service, which cannot be detailed here. However, we were able to confirm that he had not traveled recently to the Middle East or any areas with endemic malaria. Based on areas traveled, mild liver involvement, and the short list of infectious causes of DAH in immunocompetent patients, leptospirosis and dengue fever were suspected. Influenza remained a possibility also as the presentation occurred during influenza season, though all military members on the ship had received annual influenza vaccination. Tick-borne illnesses, while unlikely causes of DAH, were also considered based on travel to Vermont (though seasonality was not consistent). S. aureus pneumonia also was a possibility, made less likely by the presence of viral prodrome unless it had occurred as a complication of influenza. Family history was unknown as the patient had been adopted from Romania at birth, and there were no known sick contacts or disease outbreaks on his submarine.
The patient was empirically started on high dose intravenous steroids for possible vasculitis; extensive evaluation for rheumatologic disease excluded granulomatosis with polyangitis (Wegener's syndrome), anti-glomerular basement membrane disease (formerly 'Goodpastures' syndrome), systemic lupus erythematosus, antiphospholipid antibody syndrome, systemic sclerosis, and mixed connective tissue disease. Lung biopsy was not pursued due to high risk of bleeding while on ECMO.
Based on epidemiologic risk factors, clinical presentation, and severity of illness, empiric antibiotic therapy with vancomycin, ceftriaxone, azithromycin, doxycycline, and oseltamivir was chosen to cover for community acquired pneumonia (including typical and atypical pathogens and MRSA), leptospirosis, tick-borne infections, and influenza. Prior to confirmation of full recent travel history, contact, droplet, and airborne isolation was instituted due to concern for MERS-CoV (Middle East respiratory syndrome coronavirus).
Testing for acute and chronic HIV, hepatitis B, and hepatitis C was negative. No respiratory viruses were identified by PCR from nasal swab or bronchoalveolar lavage (BAL). Cultures of blood and BAL specimens for bacterial and fungal pathogens were also negative. Other negative tests included: thick and thin blood smears for malaria, Legionella and Streptococcus pneumoniae urinary antigens, serum CMV PCR, Lyme IgM, and IgG, IgM, and PCR for Ehrlichia chaffeensis and Anaplasma phagocytophilum. Mycoplasma IgG was positive, but IgM and PCR were not. Hantavirus IgG was also positive with negative IgM.
Two days into the patient's admission to the tertiary hospital, his family recalled an important clue - they showed the medical team a digital photograph of the patient covered in mud that he had sent approximately two weeks prior to illness onset [Fig. 2]. He had participated in the "Warrior Dash" in Hawaii. The event consists of fourteen outdoor obstacles, several of which involved full body exposure to mud or fresh water. Consistent with clinical suspicion, IgM for Leptospira was positive. The Centers for Disease Control and Prevention and Hawaii Department of Health (HI DOH) Disease Investigation Branch were made aware, and they provided confirmatory testing. A four-fold increase in IgM titers from acute to convalescent phase, as well as PCR positive for Leptospira interrogans serovars Icterohaemorrhagiae and Mankarao, further bolstered the diagnosis. The dominant serovar in HI is icterohaemorrhagiae; therefore transmission likely did occur while the patient was in HI, during participation in the 'Warrior Dash' two weeks prior to symptom onset. The presence of serovar mankarao is consistent either with co-infection or with cross reactivity on testing. Per HI DOH, there were no other known cases occurring in association with this event.
By the patient's sixth day on ECMO he had a significant radiographic and clinical improvement with no further evidence of DAH. He was decannulated from ECMO and endotracheally extubated the following morning. Total time on ECMO was 126 h. Two days later he was discharged from the intensive care unit and he left the hospital shortly after. At follow up one month later, patient reported being weak compared to his baseline (could 'only' perform 20 push-ups). Following a three to five month process of medical clearance, the patient was able to return to active duty for the US Navy (Fig. 3). He notes that on hikes in HI he routinely warns people he encounters of the risk of leptospirosis.