Metapneumovirus-Induced Myocarditis Complicated by Klebsiella pneumoniae Co-Infection: A Case Report

Introduction

Human metapneumovirus (hMPV), an emerging respiratory virus first isolated in 2001 [1], has been reported worldwide. hMPV accounts for 6–40% of acute respiratory illnesses in hospitalized and outpatient children globally [2]. In Taiwan, 16.8% of children hospitalized with bronchiolitis are infected with hMPV [3]. In the northern hemisphere, outbreaks of hMPV predominantly occur during the winter and spring months, whereas in the southern hemisphere, they primarily occur in June and July [4,5]. Most children experience an hMPV infection before the age of 5 years [6,7]. While hMPV infections can reoccur throughout adulthood, they are usually asymptomatic or mild in healthy adults [8]. Elderly people and adults with underlying medical conditions are at higher risk for HMPV complications [2]. As a nonsegmented, negative-sense RNA virus [1], it primarily causes upper and lower respiratory tract infections in children [9] and threatens the health of elderly and immunocompromised individuals [6]. The clinical features of the illness caused by hMPV infection range from mild upper respiratory tract infection to life-threatening severe bronchiolitis and pneumonia [10,11]. However, rare cases have highlighted hMPV infections manifesting in sites beyond the respiratory system, including cardiac impairment. Acute myocarditis secondary to hMPV infection has only been described in a few adult case reports; this condition has a good prognosis when not accompanied by other infections [12–14]. Here, we present a case of severe pneumonia and myocarditis caused by hMPV infection in an elderly patient. While previous studies have reported cases of acute myocarditis caused by metapneumovirus, this case is notable for its severe outcomes, which may be associated with concurrent severe pneumonia and underlying comorbidities. This case not only highlights the need to consider hMPV in differential diagnoses of myocarditis in elderly patients but also underscores the necessity for further research on hMPV-related cardiac complications.

Case Report

A 68-year-old man was sent to our ED because of fever, a productive cough, and progressive dyspnea for 1 day. Upon arrival at our hospital, he had clear consciousness, tachycardia (143 beats/min), tachypnea (28 breaths/min), blood pressure within the normal range (106/88 mmHg), and fever (38.4°C). Neither chills, muscle soreness, nor limb weakness were noted. He had no recent travel, tick bites, or acute upper respiratory infections. He had not been in direct contact with any birds, poultry, or horses. He had a 10-year history of underlying diabetes mellitus and hypertension and was on regular medication with metformin 500 mg and valsartan 80 mg daily. He also had liver cirrhosis with chronic hepatitis B infection and received 0.5 mg/d entecavir regularly. He had no tuberculosis or lung cancer. He was a former smoker, having quit 10 years ago, and had a history of drug addiction.

On physical examination, lung auscultation revealed crackles in the right lung fields. Laboratory tests revealed that the white blood cell (WBC) count was 3240/µL, with 49% neutrophils (10% of the band form) and 33% lymphocytes. His lac-tate level was 12.2 mmol/L, and he had metabolic acidosis and a high procalcitonin level (50.75 mg/dL). His troponin-I concentration was 248 pg/mL, his CPK concentration was 662 U/L, and the CKMB concentration was 1.9 ng/mL. The platelet count was 221 000/µL. BUN and creatinine were 39 mg/dL and 2.34 mg/dL, respectively. AST was 111 IU/L. Electrolytes were within the normal range. Urine analysis revealed amber-colored urine with a bacteria count of 296.6/µL and no pyuria.

A chest X-ray revealed alveolar infiltration in the right middle lobe (Figure 1). An electrocardiogram (ECG) showed sinus tachycardia (Figure 2). Under the tentative diagnosis of sepsis with pneumonia, piperacillin/tazobactam (4500 mg) was administered as empiric antibiotics. This was to broadly cover the potential pathogen of community-acquired pneumonia and even Pseudomonas aeruginosa. His clinical condition deteriorated rapidly to septic shock with severe hypoxemia (saturation 85–89% under non-re-breathing mask) and hypotension (78/49 mmHg). Non-invasive cardiac output hemodynamic monitor showed low stroke volume (43 mL; normal range 60–100), low systemic vascular resistance (935 dyn·s/cm5; normal range: 900–1600), and low index of contractility (23.4; normal range: 30–50). Epinephrine was administered with an infusion rate of 1.28 mg/h (0.33 mcg/kg/min) via a central vein catheter. After tracheal intubation and ventilator-assisted ventilation, he was transferred to the MICU for further treatment (on day 0).

In the MICU on day 0 (Figure 3), arterial blood gas analysis initially revealed a pH of 7.322, PO2 of 315.3 mmHg, PCO2 of 23.3 mmHg, HCO3 of 11.8 mmol/L, and FiO2 of 60%. Due to persistent hypotension (75/51 mmHg), vasopressin with an infusion of 0.96 unit/h and epinephrine with an infusion of 160 mg/h were administered. With progressive dyspnea, arterial blood gas analysis revealed a pH of 7.23, PO2 of 114.2 mmHg, PCO2 of 46.2 mmHg, HCO3 of 18.9 mmol/L, and FiO2 of 100%. Chest X-ray revealed cardiomegaly and progressive infiltration in the bilateral lung. Moderate ARDS was diagnosed based on poor PaO2/FiO2 ratio of 114.2.

On day 1, the WBC count was 3070/µL, and BUN and creatinine were 38 mg/dL and 1.78 mg/dL, respectively. His AST level increased to 2035 IU/L, and his ALT level was 679 IU/L. Troponin-I (2167 pg/mL), CPK (3319 U/L), and CKMB (182 mg/ dL) were elevated. The lactate concentration was 18.1 mmol/L (Table 1). ECG revealed diffuse S-T elevation. Cardiac echocardiography (Figure 4) revealed a left ventricular ejection fraction of 15% with global left ventricular hypokinesis and blood stasis within the LV, which indicated acute heart failure with reduced ejection fraction, suspected stress cardiomyopathy, and myocarditis. Due to his severe cardiopulmonary failure, characterized by refractory hypoxemia and cardiogenic shock, despite maximal conventional therapy, ECMO was initiated via the right femoral artery and right femoral vein. The initial ECMO settings included a FiO2 of 1.0, an air flow of 2 L/min, and a CO of 2 L/min, with a pump speed of 2140 RPM. For the ventilator, the FiO2 was set at 90%, the tidal volume at 6.5 mL/kg, and the respiratory rate at 35 breaths per minute. The temperature was maintained at 37°C. A CAG (Figure 5) was performed to rule out acute myocardial infarction and showed no significant vessel obstruction. Due to the need to reduce cardiac afterload, IABP was inserted into the descending aorta. However, with progressive hypotension, he ultimately died on the morning of day 2. The main cause of death was refractory cardiogenic shock despite aggressive ECMO and IABP support. Acute myocarditis led to severe and irreversible cardiac dysfunction, which ultimately resulted in multi-organ failure.

Concerning the presence of the pathogen, the results of 2 sets of peripheral blood cultures and urine cultures during episodes of fever were negative. FilmArray® Pneumonia Multiplex PCR Panel was performed to identify the causative pathogens. The result showed a positive finding for hMPV and negative findings for parainfluenza virus (types 1–4), adenovirus, rhinovirus, enterovirus, Mycoplasma pneumoniae, Bordetella parapertusis, and Bordetella pertussis. Moreover, sputum culture revealed the pathogen Klebsiella pneumoniae with KeyMyth Klebsiella pneumoniae Serotype 1 (Key Myth Biotech, Co. Ltd. Taiwan). The drug sensitivity results (Table 2) indicate that Klebsiella pneumoniae was sensitive to piperacillin/tazobactam, with a minimum inhibitory concentration (MIC) of ≤4. The final diagnoses were co-infection with Klebsiella pneumoniae and metapneumovirus, severe community-acquired pneumonia, type I respiratory failure, acute respiratory distress syndrome (ARDS), and myocarditis.

Discussion

CLINICAL CHALLENGES OF A RARE CO-INFECTION:

Among hospitalized adults with respiratory viral-bacterial co-infections, Klebsiella species had the third highest mortality rate, ranging from 18.9% to 22.0% depending on the virus, and had a low prevalence about 5–10% [15]. The co-infection of Klebsiella pneumoniae and human metapneumovirus presents a unique clinical challenge due to its rarity and the potential for severe respiratory complications. This case is significant as it demonstrates how such infections can exacerbate patient conditions, leading to outcomes like septic shock and ARDS. While Klebsiella pneumoniae is a known pathogen in community-acquired infections, its combination with meta-pneumovirus has not been extensively reported, highlighting the importance of this case as a contribution to existing medical knowledge.

MECHANISM OF HMPV INFECTION:

hMPV enters host cells by fusing with the cell membrane via the viral surface fusion (F) glycoprotein. HMPV F attaches to cellular receptors and facilitates virus membrane fusion with cellular membranes during virus entry [16]. It replicates within cells and spreads by evading the immune system, inducing a weak innate response and interfering with T cell activation and pattern recognition receptors, which allows hMPV to persist in the host [17]. hMPV primarily causes respiratory infections such as bronchiolitis and wheezing, and can also lead to rare but severe extrapulmonary complications like myocarditis [12–14]. The exact mechanism of hMPV-induced myocarditis remains unclear [14]. Emerging evidence suggests that hMPV-induced myocarditis may result from both direct viral invasion of myocardial cells and an immune-mediated response [18]. The virus’s evasion of the immune system allows persistence, potentially causing direct damage to cardiac tissue. Additionally, the altered immune response may lead to myocardial inflammation through mechanisms such as molecular mimicry or bystander activation. Further research is required to fully understand these processes.

COMPARISON WITH HMPV INFECTION IN THE MYOCARDIUM:

Although hMPV infection mostly manifests via the upper and lower respiratory tract, several case reports of myocarditis caused by hMPV infection in children, elderly individuals, and immunocompromised patients have been published. Previous studies have documented cases of hMPV-associated myocarditis, but these have predominantly focused on pediatric populations or cases with favorable outcomes. Acute myocarditis secondary to hMPV infection has only been described in a few adult patients [12–14]. Weinreich et al [13] were among the first to document myocarditis caused by hMPV, in a previously healthy 25-year-old adult. Choi et al [12] described a case of myopericarditis complicated by pneumonia in a 73-year-old patient, emphasizing hMPV’s potential for severe complications in high-risk populations. More recently, Ingram et al [14] reported a rare case of sepsis-induced cardiomyopathy linked to hMPV, highlighting the unique cardiac manifestation of sepsis. In contrast to those cases with generally favorable outcomes, our case had a poor prognosis for an adult patient with hMPV myocarditis complicated with severe ARDS and concurrent infection with Klebsiella pneumoniae. Specifically, our case exhibited distinct clinical features, and a worse outcome compared to those reported in the literature. Key differences include: 1) the severity of hMPV infection; 2) the impact of co-infection on myocarditis; and 3) variations in treatment responses. Our findings suggest that when managing hMPV-related myocarditis, especially in adults, the presence of comorbidities may necessitate more aggressive management strategies to improve prognosis.

TREATMENT WITH HMPV:

The treatment approach for hMPV primarily involves supportive care and may vary based on different clinical presentations. Certain drugs, such as ribavirin, have shown potential antiviral activity against hMPV in vitro [19] but still lack large-scale clinical efficacy data [28,29]. A meta-analysis provided some supportive evidence for IVIG therapy in acute myocarditis patients, but the role of anti-inflammatory therapy, IVIG, steroids, and antiviral therapy in hMPV myocarditis is still unclear [20]. There have been case reports and in vitro studies exploring antiviral therapies such as immunoglobulins or monoclonal antibodies [21,22]. However, the exact efficacy of these treatments still requires further evaluation. The rate of concurrent bacterial lung infections or bacteremia is higher in children infected with hMPV [23] than in those infected with RSV. In the case of hMPV, antibiotics tend to be administered because of concerns regarding concomitant bacterial pneumonia, even if a bacterial pathogen is ultimately not isolated [24].

LIMITATIONS:

Initially, safety concerns precluded the myocardial and pericardial biopsies, rendering the pathologic confirmation of myopericarditis diagnosis unattainable. Additionally, cardiac magnetic resonance (CMR) imaging was omitted in this instance. CMR imaging is recognized as a pivotal diagnostic tool for myocarditis that effectively distinguishes between ischemic and non-ischemic cardiomyopathy. Although CAG and cardiac echo were performed to exclude vascular obstruction and valvular disease, distinguishing between acute myocarditis and septic cardiomyopathy presents certain challenges due to the lack of biopsy. Furthermore, the absence of bronchoscopy limited respiratory virus PCR to an upper respiratory specimen. Despite clinical alignment with hMPV pneumonia, a positive PCR result from a throat swab specimen does not necessarily indicate a lower respiratory tract infection.

Conclusions

Compared to previously reported cases of metapneumovirus-related myocarditis with a good prognosis, this case report highlights the potential for human metapneumovirus (hMPV) to cause myocardial involvement with severe consequences, particularly in patients with concurrent bacterial infections. Our patient presented with severe respiratory distress and cardiac symptoms, posing significant diagnostic challenges. A multi-disciplinary management approach was employed, including the use of ECMO and targeted antibiotic therapy. The adverse outcome observed in this case, characterized by rapid clinical deterioration and specific laboratory findings, underscores the critical need for early detection and intervention.

Further research is needed to understand the co-infection dynamics between hMPV and bacteria. The development of guidelines for early detection and management of such cases could improve patient outcomes. Although hMPV is generally associated with acute respiratory tract infections in children, clinicians should consider hMPV in the differential diagnosis of myocarditis, especially in cases with concurrent bacterial infections, to ensure timely and appropriate management.