Fatal Pneumocephalus Caused by Hypermucoviscous Hydrogenproducing Klebsiella Pneumoniae Capsular Genotype K63 in a Patient with Diabetic Ketoacidosis

Pneumocephalus resulting from cerebral infections is a rare but often deadly infection. Here we describe a fatal case of pneumocephal caused by a hypermucoviscous hydrogenproducing Klebsiella pneumoniae strain in an immunocompromised diabetic patient. Pneumocephalus is usually caused by cranio-facial trauma and occasionally by cerebral infection [1]. In particular, intracerebral air embolisms resulting from a brain abscess usually lead to poor outcomes [1,2]. Klebsiella pneumoniae is a well-known pathogen associated with respiratory infection, liver abscess and meningitis but rarely pneumocephalus [1,2]. In recent decades, only eight reports of pneumocephalus caused by K. pneumoniae in non-operative and non-traumatic patients have been described [3-10]. Interestingly, most patients were older than 50 and suffered from diabetes (Table 1), except 2 cases, of which were caused by chronic suppurative otitis media and the tuberculous spondylitis, respectively [8,9]. Unfortunately, except for the patient suffering from otitis media and another who received an emergency craniotomy, all of the other patients died within 5 days of hospitalization [8,9]..

Table 1:Cases of pneumocephalus caused by K. pneumoniae infection in non-operative and non-traumatic patients.

NA: Not Available; CSF: Cerebrospinal Fluid.

We report a case of pneumocephalus caused by hypermucoviscous H2-producing K. pneumonia infection in a 38-year-old man with diabetic ketoacidosis. The patient, who had a history hyperglycemia, was transferred to our hospital with a high fever (39 °C). He had a normal pupillary light reflex, no vomiting, diarrhea or chest tightness. Laboratory examination results were as follows: glucose, 22.07mmol/L; Total Protein (TP), 46.724g/L; Albumin (ALB), 24g/L; complement C3, 0.5g/L; complement C4, 0.05g/L; C-Reactive Protein (CRP), 325mg/L; Procalcitonin (PCT), 56.61ng/mL; HbA1c 15.4%; leukocytes, 21.1 × 10⁹ cells/L (NEU, 89.1%); CD4+, 178cells/μL; CD8+, 100cells/μL; pH, 7.198; and PCO₂, 21.5mmHg. Urine analysis revealed strong positive results for glucose, urine ketone bodies, protein and occult blood. Computed Tomography (CT) scans indicated multiple infections in both lungs, but no inflammation signals were observed in the head or abdomen. Thus, we determined the best treatment strategy to include mechanical ventilation, liquid replenishment to correct acidosis, insulin administration to lower glucose, and ceftriaxone injection to reduce any infection.

On the 2_nd day of hospitalization, the patient’s situation deteriorated rapidly, his pupillary light reflex disappeared and he became unresponsive. Two hypermucoviscous K. pneumonia strains were cultured from his sputum and blood samples. Both strains were highly sensitive to antibiotic treatment and the patient’s medication was changed to Imipenem. During the treatment, the patient’s fever dissipated, the PCT and glucose levels gradually decreased to 20.12ng/mL and 13.66mmol/L, respectively, the pH recovered to 7.316 and even the blood sample collected on the 6th day was negative for bacterial culture. However, CT scans on the 6th day revealed anggravated lung infection, cerebral hernia, multiple pneumocephalus and massive subarachnoid hemorrhage. Cerebro Spinal Fluid (CSF) tests showed leukocytes numbers of 71,298cells/μL and rythrocytes of 97,000cells/μL. Subsequently, the CSF was found to be positive for K. pneumonia by both culture and metagenomic next generation sequencing. Interestingly, the K. pneumonia strain grew only on the edge of the CSF inoculation area but was absent in the center (Figure 1). Unfortunately, this patient died from the severe cerebral infection on the 9th day after onset.

Pneumocephalus caused by K. pneumoniae infections is a rare but potentially fatal disease more commonly seen in older patients with diabetes [3-7,9]. In this study, the patient was young, he had no operative or traumatic history, but was immunocompromised. The hypermucoviscous K. pneumoniae strains isolated from his sputum, blood and CSF samples showed the same antibiotic sensitive profile to carbapenems, cephalosporins, quninolones, aminoglycosides and sulfonamides. All three strains belonged to the ST111 and capsular genotype K63 and exhibited 100% identical pulse field gel electrophoresis patterns Figure 1, which confirmed that the K. pneumoniae strains were from a single clone. The antibiotic treatment was partially effective because the pathogen had already been cleared away from the blood stream and had been greatly reduced in the CSF. However, this strain was hypermucoviscous, and also resulted in excessive gas formation. Indeed, the results of the string test indicated the viscous nature of the culture, and which could not be successfully precipitated by centrifugation at 12,000RPM in the Luria Broth culture. The gas collected from the anaerobic bottle was ~60mL after 36h incubation.

Figure 1:A, Pulse Field Gel Electrophoresis (PFGE) result of the K. pneumonia strains. Lanes 1–3, the K. pneumonia strains isolated from sputum, blood and CSF samples, respectively. B, head CT image acquired on the 6^th hospitalization day of the patient. The white arrow indicates the cerebral air embolism. C, culture results of the CSF sample on a blood-agar plate. The black arrow indicates the initial inoculation area.

According to gas chromatography analysis, it was mainly composed of N₂ (3.3×10⁵mg/m³), CO₂ (2.8×10⁵mg/m³), H₂ (7.4×10⁴mg/m³) and CO (7.5×10²mg/m³). Based on these results, we speculated that the young diabetic patient was infected by a hypermucoviscous K. pneumoniae strain by accident. Unfortunately, as the patient was immunocompromised, the pathogen easily entered the blood and further penetrated the blood-brain barrier to cause severe cerebral infection. Although the infection was controlled with antibiotics, the large amounts of mucous and gases produced by the K. pneumoniae strain proved deadly.

In conclusion, we described a fatal case of pneumocephalus caused by K. pneumoniae cerebral infection in a diabetic patient. Although sensitive to antibiotics, great attention should be paid to the large amounts of mucous and gas producing K. pneumoniae strains in diabetic patient.

We appreciate the collaboration of the fifth affiliated hospital of Wenzhou Medical University and the staff of Lishui Center for Disease Control and Prevention. Particularly, we thank doctor Yuejin Huang for consultation of this case.

This research was supported by the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China under Grant No. LHDMZ23H190001.

JH and JX designed the study. JC, JX, XC and JH participated in the laboratory experiment. JH evaluated clinical presentations of all the strains. SX evaluated the CT scan. JX, JC, XH, and RW participated in the data collection and analysis. JH, JX wrote the manuscript. All authors read and approved the final manuscript.

The study was approved by the Research Ethics Board at the fifth affiliated hospital of Wenzhou Medical University. Strains analyzed in this study were collected from clinical routine. No written informed consent was acquired due to the retrospective nature of the study and the information was de-linked.

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