Zhenfeng Lu, Aiping Zhang, Jingsheng Guo, Haibin Ni

Department of Emergency Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, China

Community-acquired pneumonia is a common disease caused by a variety of pathogens.Tropheryma whipplei(T.whipplei) is a rare pathogenic bacterium,few cases have been reported.George Hoyt Whipple described Whipple’s disease as a chronic infectious disease affecting multiple organ systems for the first time in 1907.[1]The symptoms of classical Whipple’s disease (CWD) include arthralgia, diarrhea,steatorrhea, weight loss, lymphadenopathy, abdominal pain, hypoalbuminemia and anemia,[2]affecting the gastrointestinal tract, bones and joints, cardiovascular system and nervous system, and is rarely associated with pulmonary infections.[2,3]Currently, the incidence rate is estimated to be between 1 and 6 new cases per 10,000,000 people per year worldwide.[4]Additionally,it is almost impossible to diagnoseT.whippleithrough a sample culture.[5]Therefore, clinicians are prone to miss the diagnosis.Herein, a rare severe pneumonia case ofT.whippleiinfection combined withLegionella pneumophilawas reported, and the experience in diagnosing and treating was illustrated.

CASE

A 62-year-old woman with a history of hypertension and diabetes mellitus visited the emergency department with recurrent fever, back pain and weakness for one day.During the course of the disease, there were no headaches, chest pains, nausea, vomiting, abdominal pain, diarrhoea, urinary frequency or urgency.The patient had no history of cerebral infarction, heart disease, acute or chronic infections (such as hepatitis and tuberculosis),and no known drug allergies.

On arrival at the emergency department on 8thDecember 2022, the patient developed dyspnoea, cough and drowsiness and had a fever between 38.5 ℃ and 39.2 ℃.Her vital signs on admission to the resuscitation room were as follows: pulse rate 117 beats/min;respiratory rate 25 breaths/min; blood pressure 142/90 mmHg (1 mmHg=0.133 kPa) and oxygen saturation on room air 80%.Dry and wet rales were heard in both lungs.The lower extremities were symmetrical and non-edematous.Furthermore, no rash was observed.The laboratory test results were as follows: white blood cell (WBC) count 16.61×109/L, neutrophils 91.9%,lymphocytes 3.9%, C-reactive protein (CRP) 345.91 mg/L; the serum potassium, calcium, cardiac enzymes,troponin T levels, liver and kidney functions were within the normal ranges; procalcitonin (PCT) 3.1 ng/mL;D-dimer 7.46 μg/mL; and negative COVID-19 nucleic acid and antibodies.Arterial blood gas analysis showed hypoxia on room air (pH 7.52, PO241.2 mmHg, PCO222 mmHg, HCO3-21.8 mmol/L), and the N-terminal pro-brain natriuretic peptide (NT-proBNP) was 167 pg/mL.In addition, extrathoracic echocardiography showed normal left ventricular contractility with an ejection fraction of 56.6%.The chest computed tomography (CT)revealed infectious lesions in lungs, an enlarged heart,and signs of pulmonary hypertension (Figure1 A).

Cardiogenic etiology was excluded by cardiac enzymes, NT-proBNP, electrocardiogram and echocardiography.As the patient was in respiratory failure, non-invasive ventilation was performed.In addition, the patient had a fever, cough, elevated WBC count and PCT levels, which suggested a serious infection.Thus, the antibiotic piperacillin-tazobactam sodium was carried out empirically.Bacterial cultures of sputum, blood and urine were performed to determine the pathogenic microorganisms.As the patient experienced a drop in blood pressure, appropriate fluid resuscitation and a small dose of norepinephrine (2–4 μg/min) were administered to maintain blood pressure, and the patient was then admitted to intensive care unit for further observation.

Despite these treatments and supportive care, the clinical status of the patient deteriorated on the day after admission, accompanied by a drop in finger pulse oxygen, recurrent hyperthermia (39.9 ℃) and an increase in norepinephrine dose.With non-invasive ventilatorassisted ventilation, her oxygen saturation dropped from 96% to 87%.Her chest CT findings (Figure 1B)indicated large solid and ground glass shadows in both lungs, with a predominantly subpleural distribution and an increase in the extent of lesions in both lower lungs compared with before.Considering the poor outcome, the possibilities of poor sputum drainage and a drug-resistant bacterial infection were analyzed.The antibiotics were changed to meropenem.Meanwhile,endotracheal intubation with invasive mechanical ventilation and fiber-optic bronchoscopy was performed.Fiberoptic bronchoscopy revealed airway mucous membrane edema as well as a small amount of yellowwhite sputum in the lower bronchial segment of both lungs.The oxygen saturation of the patient maintained at 99% after the fiberoptic bronchoscopy.Additionally,yellowish-white purulent sputum was collected for nextgeneration sequencing (NGS).The results of NGS were as follows: Whipple’s adoptive barrier sequence number 280,426; andLegionella pneumophilasequence number 3,949.Mycoplasma,Chlamydia,Mycobacterium, fungi,parasites, and other types of bacteria were not detected.

After the identification of the pathogen, moxifloxacin was added to treat theLegionella pneumophilainfection.The dyspnoea, hypoxemia and temperature of the patient improved significantly within 3 d.After 4 d of treatment,the overall condition of the patient improved significantly and she was extubated and placed on high-flow oxygen therapy for further observation.Additionally, the patient was permitted to engage in physical activity, and she did not exhibit any noticeable signs of shortness of breath.Moreover, her PCT and leukocyte levels decreased significantly: WBC count 8.08×109/L, CRP 77.84 mg/L; and PCT 0.47 ng/mL.On the 8thday after admission,the patient was transferred to the general ward for further management.She was discharged 13 d after admission and oral moxifloxacin was administrated.At discharge, the patient had only a little dry cough, no fever, no shortness of breath and no low back pain.She was followed up by telephone and was able to perform normal physical work.

DISCUSSION

During the treatment of infectious diseases, early identification of the pathogenic microorganism is crucial when patients present with increased symptoms and hemodynamic instability.Herein, the patient with dyspnoea, high fever, malaise and back pain was admitted to our hospital and was treated with antibiotics.However, as the patient’s initial treatment was not effective, the antibiotics might fail to cover the full range of microorganisms.Thus, the treatment was immediately changed.Considering that bacterial culture is timeconsuming process and with low sensitivity, the coinfection ofT.whippleiandLegionella pneumophilawas clarified by using NGS of bronchoalveolar lavage fluid which is fast and sensitive.[6]After that, a reasonable treatment plan was quickly formulated, and the patient eventually achieved a favorable outcome.

T.whippleiis a rare pathogenic bacterium with only a few reported cases.It is a Gram-positive actinomycete widely distributed in the natural environment and is unlikely to cause disease in healthy humans, but can cause a chronic and multisystemic infectious disease known as Whipple’s disease.In addition, in the context of CWD, the rare chronic infection withT.whippleihas an estimated incidence of 1 in 1,000,000.[7]The oro-oral and fecal-oral routes of transmission are the most likely between humans.[8]Besides oro-oral transmission, there is some evidence suggesting respiratory transmission.[9,10]

Gastrointestinal symptoms such as diarrhea and abdominal pain, joint symptoms such as arthralgia or arthritis, and weight loss are the most common features of CWD.Other symptoms include low fever, anemia and adenopathy.Respiratory symptoms are rare.[11]Our patient presented with acute onset of symptoms, rapidly developing a high fever, cough, respiratory failure, back pain and hypotension.Since the patient did not have typical symptoms of infection, the diagnosis might have been missed without NGS.Most reported cases are also diagnosed using NGS, making it a potential tool for better detection of respiratory pathogens.[12-14]

Whipple’s disease can be fatal without appropriate antibiotic treatment.The antibiotics included penicillin,streptomycin, tetracycline, ceftriaxone, meropenem,co-trimoxazole, doxycycline and hydroxychloroquine.Currently, some treatments are based on trials involving a relatively small number of patients.[4,15]We used piperacillin-tazobactam initially, but the patient’s condition continued to deteriorate.Then, the antibiotic was changed to meropenem.However, the high fever recurred, which was considered to be related to the patient’s co-infection withLegionella pneumophila.At last, meropenem was combined with moxifloxacin for therapy, and a favorable outcome was eventually achieved.

CONCLUSIONS

Cases of severe pneumonia caused by a combination ofT.whippleiandLegionella pneumophilahave not been reported.In clinic, some rare pathogens are difficult to diagnose, since they have a wide range of non-specific manifestations.It is of great significance to choose suitable antibiotics, especially when dealing with multiple bacterial co-infections.For patients with severe infections and unknown pathogens, early NGS is recommended to guide the decision-making of treatment plan.

Funding:None.

Ethical approval:The study team obtained the patient’s consent and passed the hospital ethics committee.

Conflicts of interest:The authors declare no competing interests.

Author contribution:All authors contributed substantially to the drafting and revision of this manuscript and approved its contents.