A 69-year-old woman with a slight shortness of breath was admitted to our hospital (December 26th, 2020), complaining of weakness in her arms and legs for the last week. Almost all the typical symptoms, including fever, cough, rhinobyon, previous asthma, COPD, and poor working or living environment conditions, such as smoking and contact with pets and poultry, were denied by herself. Additionally, she did not contact suspected COVID-19 cases, with negative PCR results for COVID-19 (Table 1). She suffered from RA for 30 years, taking a long-term course of steroids. Recently, as the symptoms progressed, the therapeutic schedule was changed to include methotrexate, leflunomide, and prednisone. Given the suspicion of peripheral neuropathy or anemia, she was treated with neurotrophic agents. Upon admission to our hospital, the physical examination found a body temperature of 36.2 C, blood pressure of 142/83 mmHg, pulse of 105 beats per minute, and a respiration rate of 20 per minute. Fine moist rales appeared in the lower lobes of the lungs. She presented muscle strength of grade 5 for upper limbs and grade 3 for lower ones.
Her condition deteriorated at night, with sudden polypnea and low-grade fever. Due to hypoxemia (pO2 68 mmHg, pCO2 21.6 mmHg), the patient was given oxygen therapy with a mask and atomization inhalation. The computed tomography (CT) scan showed diffused effusion and ground glass opacity (GGO) in both lungs (Figure 1). Other laboratory tests revealed three series decrease in peripheral blood, especially in lymphocyte counts, abnormal renal function with creatinine value of 230.5 mumol/L, and blood urea nitrogen value of 16.6 mmol/L.
Given the rapid disease progression, the patient was transferred to our intensive care units for further treatment at midnight on December 28th. She was sober but extremely fatigued, breathless, weak in all limbs, with a mild fever. The vital signs indicated a heart rate of 138 per minute, saturation of pulse oxygen (SpO2) of 85% on oxygen therapy with mask, and respiration rate of 31 per minute. Based on all the clinical symptoms and physical examinations, the diagnosis of acute respiratory failure was established. Intubation and mechanical ventilation were performed. At the same time, invasive blood pressure showed 66/42 mmHg, with sequential organ failure assessment score of 18. So, she was considered to be in the status of septic shock. Fluid resuscitation and vasoactive drugs were given following the 1-h bundle principles. To obtain etiological specimens, she underwent electric bronchoscopy with BALF collection. The BALF was tested through various methods, including culture, smear, GeneXpert MTB, and galactomannan test. Considering that the patient was highly suspected of opportunistic infections, such as PJP or cytomegalovirus infection, the mNGS for pathogen detection from serum and BALF were carried out immediately. Meanwhile, she was given oral trimethoprim/sulfamethoxazole (TMP/SMX, 320/1,600 mg q.i.d.) and intravenous acyclovir. Besides, other bacterial infections could not be excluded because of increasing inflammatory biomarkers, and she was given broad-spectrum antimicrobial therapy. Continuous renal replacement therapy was also performed for acute kidney injury.
Bone marrow biopsy was carried out on the second day of hospitalization (Day 2). The results revealed that the hemophagocyte was detected in the smear (Figure 2). It was inferred that the condition could be associated with severe infection.
On the third day, the sputum, urine, and blood cultures returned with negative results (Table 1). Gram stain of the BALF revealed many Gram-negative organisms. mNGS revealed P. jirovecii in both serum and BALF with reads per million (RPM) of 17 and 437 (Figure 3), while other diagnostic tests did not detect any pathogenic microorganism. The mtSSU region of P. jirovecii was subsequently detected by qPCR using the same samples (Figure 3). Four out of the eight samples gave positive results. The PCR products were sequenced by Sanger and finally identified as P. jirovecii, confirming the mNGS results. The results were verified by qPCR using the same samples. Accordingly, the patient was treated with TMP/SMX, caspofungin, and thymalfasin to boost immunity.
Corticosteroids could suppress the acute inflammatory process. However, the X-ray showed that effusion did not decrease as expected. Despite attempts at optimizing gas exchange by prone position ventilation for nearly a week, the arterial blood gas analysis indicated that pO2/FiO2 ratio was still below 100 mmHg, which made it necessary to take a rescue extracorporeal membrane oxygenation (ECMO) therapy. Mechanical ventilation was switched to an ultra-protective strategy using pressure control ventilation. On the 17th day of admission, a chest X-ray revealed an obvious decrease in exudation. She was successfully de-cannulated after 9 days of V-V ECMO support. During the 21-day treatment, the DNA reads of P. jirovecii by mNGS using both serum and BALF disclosed a dramatic increase since the medication of TMP/SMX, then declined gradually (Figure 4).
Unfortunately, acute hepatic failure occurred. Plasma bilirubin levels remained high despite the support of plasma exchange and resin plasma perfusion adsorption. mNGS of serum and BALF detected Acinetobacter baumannii on January 13th and Klebsiella pneumoniae on January 19th (Table 1), indicating nosocomial infection. Drug susceptibility tests revealed multidrug-resistant bacteria infection (A. baumannii resistant to quinolones, beta-lactam antibiotics, sulfonamides, and aminoglycosides; K. pneumoniae resistant to quinolones, beta-lactam antibiotics, and sulfonamides), leading to prolonged stay in hospital. Finally, the patient died on the 29th day of admission.