Pulmonary embolism triggered by cold agglutinin syndrome in mycoplasma
pneumoniae pneumonia
Key words: Mycoplasma pneumoniae; pulmonary embolism; cold agglutinin
syndrome
To the Editor
Mycoplasma (M.) pneumoniae is a common pathogen causing respiratory
infections in children. Pulmonary embolism is a rare complication that
may be life-threatening if not diagnosed early and treated promptly.
Here, we report the case of an 11-year-old patient with pulmonary
embolism associated with M. pneumoniae pneumonia. The patient developed
uncorrectable hypoxemia and received venovenous extracorporeal membrane
oxygenation treatment. Although the mechanism of thrombosis after M.
pneumoniae infection remains unknown, an increase in the cold agglutinin
titer indicates that cold agglutinin syndrome might be the mechanism of
this pathological change. We thought that patients who have positive
cold agglutinin after M. pneumoniae infection should be monitored for
the possibility of thrombosis formation.
Introduction
Mycoplasma (M.) pneumoniae is responsible for approximately 40% of
community-acquired pneumonia cases in children aged > 5
years, and approximately 20% of infections are asymptomatic. A rare
complication is a pulmonary embolism, which may be life-threatening if
not diagnosed early and treated promptly. The mechanism is unclear, but
includes autoimmune or cytokine-mediated vasculitis, immune
dysregulation or induction of a procoagulant activity-mediated
hypercoagulable state, a decline in anticoagulant activity, and the
formation of antiphospholipid antibodies.[1] Most cases are treated
conservatively, and there are few reports of the use of extracorporeal
membrane oxygenation (ECMO). Here, we report a case of M. pneumonia with
persistent hypoxemia that was treated with venovenous (VV) ECMO. Cold
agglutinin syndrome and pulmonary infarction were observed during
treatment. Our study shows that the relationship between cold agglutinin
syndrome and mycoplasma infection or its impact on ECMO treatment
(including the use of blood products) is worth exploring further.
Case Presentation
A previously healthy 11-year-old Chinese boy had a history of 10 days of
nonproductive cough, fever, and half days of dyspnea. After 6 days of
intravenous antibiotics (Azithromycin and Cefmetazole sodium) in the
outpatient clinic, he developed dyspnea, his C-reactive protein level
was raised to 68.36 mg/L. The patient was hospitalized because of
cyanosis aggravation. On admission, the patient was found to be using
his accessory muscles with pulse oximetry 90% under non-invasive
ventilation ( FiO2 50% and 30 L/min oxygen flow). Chest examination
revealed decreased air entry, dullness to percussion, and increased
vocal fremitus over the right lung field, with normal breath sounds over
the left. Throat swabs showed M. pneumoniae DNA positivity. Chest
computed tomography (CT) showed bilateral infiltrates, partial
consolidation mainly in the lower lobes, and pleural effusion on the
right side. There was no significant family history or tuberculosis
contact, and specifically, no evidence of thromboembolic disease.
The patient received intravenous levofloxacin and intravenous
methylprednisolone (2 mg/kg, q12h). On the second day of admission, the
patient suffered a progressive exacerbation of dyspnea; he received two
consecutive bedside bronchoscopy treatment, and formation of bronchial
casts could be seen on both sides of the tracheobronchial tree. Tests of
bronchoalveolar lavage fluid showed positive M. pneumoniae DNA. However,
his respiratory status contributed to worsen, oxygen saturation could
not be maintained with mechanical ventilation; therefore, he received VV
ECMO. Heparin was used as an anticoagulant during ECMO treatment. On day
four of admission, blood tests showed that the red blood cell count,
mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and
mean corpuscular hemoglobin concentration (MCHC) could not be measured,
and the hemoglobin level gradually decreased to 85 g/L. Considering the
presence of erythrocyte agglutination, the cold agglutinin titer was
measured as 1:128, a diagnosis of cold agglutinin disease was made.
After 4 days of treatment, the patient was weaned off the ECMO.
Subcutaneous low molecular weight heparin was administered because of
the relatively high levels of D-dimer (ranging from 2000 to 4000 µg/L).
After the patient’s vital signs were stable, he underwent pulmonary
angiography and pulmonary emboli were found in the branches of the
pulmonary artery on chest contrast-enhanced CT (Figure 1A 1C). We
decided to continue administering subcutaneous low-molecular-weight
heparin as anticoagulant therapy. No thrombosis of the abdomen or site
of catheter placement was detected on ultrasound. Contrast-enhanced CT
of the chest showed that the pulmonary emboli had decreased before
discharge. The patient was discharged with the requirement for
low-molecular-weight heparin. The coagulation function returned to
normal, and chest CT findings were almost normal at the 1-month
follow-up (Figure 1B 1D).
Discussion
The clinical manifestations of pulmonary embolism in children,
especially young children, are generally nonspecific and often mimic the
clinical symptoms of the underlying disease. The most frequent symptoms
are dyspnea, chest pain, and cough.[2]; therefore, many thrombotic
events may be missed without cardiorespiratory deterioration. However,
the mechanism of thrombosis after M. pneumoniae infection remains
unclear. Three mechanisms are currently considered to explain: (1) M.
pneumoniae is present at the site of inflammation and local inflammatory
cytokines induced by the pathogen; (2) M. pneumoniae is not present at
the site of inflammation and immune modulations, such as autoimmunity or
formation of immune complexes, play an important role; and (3) M.
pneumoniae cases systemic hypercoagulable state and/or decreasing
coagulation inhibitors.[1]
Cold agglutinin disease (CAD) is driven by cold agglutinins which are
IgM autoantibodies binding to the I antigen on the surface of red blood
cells (RBCs) at or just below the core body temperature.[3] The I
antigen is contained in long-chain sialo-oligosaccharides, which serve
as receptors for M. pneumoniae. These IgM antibody/antigen complexes
interact with the C1 complex to activate the classical complement
pathway, leading to the deposition of C3b, iC3b, and C3d opsonins on the
RBC membrane. Thrombosis has largely been attributed to disruption and
loss of the erythrocyte membrane, resulting in surface exposure of
negatively charged phosphatidylserine (PS), which provides a surface for
the formation of tenase and prothrombinase complexes. Increased surface
PS also increased endothelial adherence and, therefore, could disrupt
endothelial anticoagulant properties. Other factors, such as
cytokine-induced expression of monocyte or endothelial tissue factors,
increase the incidence of venous thromboembolism.[4] Agglutination
of RBCs also increases blood viscosity , causing reduced blood flow and
stasis, which may contribute to the gradual formation of venous
thrombosis.[3]
However, cold agglutinin syndrome in this child appeared during ECMO
treatment, and pulmonary embolism was confirmed after the withdrawal of
ECMO treatment, which made it difficult for us to connect cold
agglutinin syndrome with pulmonary embolism. Central venous catheters
are the most important risk factor for thromboembolism in
children.[5] The following are the reasons why we consider the
occurrence of pulmonary embolism associated with cold agglutinin
syndrome: 1) Chest CT showed bilateral infiltrates, partial
consolidation, and pleural effusion before ECMO treatment, which is the
chest imaging change in the early stage of pulmonary thrombosis, and the
area of lung involvement is not sufficient to cause severe hypoxemia,
which could be explained by pulmonary embolism. 2) In ECMO treatment,
the patient continued to receive heparin anticoagulant therapy and
maintained blood hypocoagulability, which is contrary to our belief that
cold agglutinin syndrome causes pulmonary embolism. 3) After
anticoagulant treatment during ECMO, hypoxemia quickly resolved. ECMO
treatment lasted only 4 days, which was far from the treatment process
of acute respiratory distress syndrome caused by lung parenchymal injury
due to M. pneumoniae. The hypoxemia was more in line with the
manifestation of pulmonary embolism than with lung parenchymal injury
caused by severe pneumonia.
In summary, a diagnosis of pulmonary embolism could easily be missed in
a patient with M. pneumoniae pneumonia, whose symptoms of chest pain,
shortness of breath, and pleural effusion could easily be attributed to
pneumonia. Cold agglutinin disease triggered by mycoplasma infection may
be the cause of pulmonary embolism. Patients with symptoms of pulmonary
embolism and positive cold agglutinin after M. pneumoniae infection
should be monitored for the possibility of thrombosis. Contrast-enhanced
lung CT, echocardiography, and blood vessel ultrasonography should be
routinely performed in such patients. It is important to diagnose
patients earlier in their disease course as the long-term prognosis of
thrombosis is good after the timely administration of anticoagulant
therapy.
References
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Authors:
Zeyu Wang MM, Ni Yang PhD, Wenliang Song PhD, Bo Wu MM, Jingli Yan MM,
Wei Xu PhD
Affiliations:
Department of Pediatrics, Shengjing Hospital of China Medical
University, Shenyang, Liaoning, People’s Republic of China.
Funding:
National Natural Science Foundation of China, Grant/Award Number:
81771621;
Corresponding author:
Wei Xu, PhD, Department of Pediatrics, Department of Pediatrics,
Shengjing Hospital of China Medical University, No. 36 Sanhao Street,
Heping District, 110004 Shenyang, Liaoning Province, People’s Republic
of China
Email tomxu.123@163.com