Pulmonary embolism triggered by cold agglutinin syndrome in mycoplasma
pneumoniae pneumonia requiring VV ECMO treatment
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
Key words: Mycoplasma pneumoniae; pulmonary embolism; cold agglutinin
syndrome
Running head: Pulmonary embolism in M. pneumoniae pneumonia
Abstract
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. Finally, the patient was cured with antibiotic
and anticoagulant therapies. Patients who have significantly increased
C-reactive protein and D-dimer levels and 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.
Extrapulmonary manifestations involving every organ system (nervous,
cardiovascular, arthritic, dermatological, digestive,
hematological/hematopoietic, musculoskeletal, sensory, and urogenital)
can occur.[1, 2] 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.[2] Most
cases are treated conservatively, and there are few reports of the use
of extracorporeal membrane oxygenation (ECMO). Herein, 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. Prior to
admission, he received azithromycin for 5 days and cefmetazole sodium
for 3 days. Chest examination revealed wheezing and prolonged expiratory
time. After treatment in the outpatient clinic for 6 days, he developed
dyspnea, his C-reactive protein level was raised to 68.36 mg/L, and
bacterial infections could not be excluded. After all the treatments,
the symptoms were not relieved. The patient was hospitalized because of
cyanosis aggravation. On admission, the patient’s vital signs were as
follows: temperature, 37.9 °C; heart rate, 126 bpm; blood pressure,
98/58 mmHg; pulse oximetry, 90%; non-invasive ventilation setting, FiO2
50%; and 30 L/min oxygen flow. On general examination, the patient was
found to be using his accessory muscles. 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. Initial laboratory tests showed a white blood cell (WBC) count of
9.6×109/L with neutrophilic predominance (82.9%), platelets 222×109/L,
hemoglobin 12.5 g/dl, C-reactive protein 74.40 mg/L, procalcitonin 0.249
ng/mL, interleukin-6 34.16 pg/mL, lactate dehydrogenase (LDH) 690U/L,
alanine transaminase (ALT) 145 U/L, aspartate transaminase (AST) 40.7
mg/L, partial thromboplastin (PT) time 13.1 s, activated partial
thromboplastin time (aPTT) 24 s, international normalized ratio (INR)
1.2, fibrinogen 3.3 g/L, D-dimer 6611 ug/L, and fibrin degradation
products (FDP) 40.7 mg/L. M. pneumoniae–specific immunoglobulin (Ig) M
(5260 U/L) and IgG levels (119.469 U/mL) were elevated, and 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
bedside bronchoscopy treatment, and formation of bronchial casts could
be seen on both sides of the tracheobronchial tree. In addition,
stenosis was present at the entrance of the pulmonary segments, and the
surface of the bronchi was partially congested and necrotic. When the
obstruction was relieved by bronchoscopy, the patient’s oxygenation
capacity continued to deteriorate and he was intubated for mechanical
respiratory support. However, his respiratory status contributed to
worsen, with lower vesicular breath sounds, and blood gas analysis
showed hypoxemia and respiratory acidosis (pH 7.16, PCO2 89 mmHg, PO2 53
mmHg, HCO3- 31.7 mmol/L). The bedside chest radiograph showed that the
pulmonary lesions did not aggravate significantly; therefore,
bronchoscopy was performed for the second time to prevent the
reformation of plastic. His oxygen saturation could not be maintained
with mechanical ventilation (peak inspiratory pressure (PIP)/positive
end expiratory pressure (PEEP) 28/8 mmHg, FiO2 1.0, respiratory rate: 25
bpm); therefore, he received VV ECMO. Tests of bronchoalveolar lavage
fluid showed positive M. pneumoniae DNA. The WBC count raised to
29.3*109/L, and the D-dimer level increased to 19809 µg/L. 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, a diagnosis of cold agglutinin
disease was made, and the titer was 1:128. We believe that refractory
hypoxemia was related to this pathological change, and hypoxemia might
have been caused by pulmonary embolism.
After 4 days of treatment, the patient was weaned off the ECMO. Oxygen
saturation was maintained via nasal cannula. Subcutaneous low molecular
weight heparin was administered because of the relatively high levels of
D-dimer (ranging from 2000 to 4000 µg/L). His fever had gone and the
levels of C-reactive protein, procalcitonin, interleukin-6, and lactate
dehydrogenase improved. He was taken off of antibiotics and
methylprednisolone on the day of extubation. 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. By the eleventh day, he was weaned off nasal
cannula oxygen inhalation. On the fifteenth day of admission, C-reactive
protein, procalcitonin, lactate dehydrogenase, ALT, and AST were back to
normal. Additionally, coagulation function returned to normal levels.
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
M. pneumoniae is responsible for up to 40% of community-acquired
pneumonia cases in children over 5 years of age.[1] Extrapulmonary
manifestations involving every organ system can occur, including cardiac
and aortic thrombi as cardiovascular manifestations; erythema nodosum,
cutaneous leukocytoclastic vasculitis, and subcorneal pustular
dermatosis as dermatological manifestations; acute cerebellar ataxia,
opsoclonus-myoclonus syndrome, and thalamic necrosis as neurological
manifestations; pulmonary embolism as a respiratory system
manifestation; and renal artery embolism as a urogenital tract
manifestation. Three mechanisms are currently considered to explain
these extrapulmonary manifestations: (1) a direct type, in which the
bacterium is present at the site of inflammation and local inflammatory
cytokines induced by the bacterium play an important role; (2) an
indirect type, in which the bacterium 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) a vascular
occlusion type, in which vasculitis and/or thrombosis with or without
systemic hypercoagulable state induced by the bacterium plays an
important role.[2, 3] Cold-agglutinin hemolytic anemia is the result
of IgM antibodies directed against the I antigens on the erythrocyte
surface.[2] Patients with cold agglutinin disease are at an
increased risk of thrombotic events.[4] To our knowledge, there have
been no cases of pulmonary embolism associated with cold agglutinin
disease in M. pneumoniae infection.
The clinical manifestations of pulmonary embolism vary and lack
specificity. Patients with mild pulmonary embolism may be asymptomatic,
while severe cases may suffer from pulmonary arterial hypertension,
unstable hemodynamics, or even sudden death.[5, 6] The most frequent
symptoms are dyspnea, chest pain, and cough.[7, 8] The clinical
manifestations of pulmonary embolism in children, especially young
children, are generally nonspecific and often mimic the clinical
symptoms of the underlying disease; therefore, many thrombotic events
may be missed without cardiorespiratory deterioration. However, the
mechanism of thrombosis after M. pneumoniae infection remains unclear.
Autoimmune vasculitis or immune-mediated inflammation of the arterial
wall may play an underlying mechanism.[9] M. pneumoniae is
transferred to the pulmonary artery, inducing cytokines (such as tumor
necrosis factor-a) and chemokines (such as interleukin-8) at the local
site through the function of lipoproteins contained in the bacterial
cell membrane, which eventually causes local vasculitic and/or
thrombotic vascular occlusion without a systemic hypercoagulable
state.[2] Mycoplasma also causes a hypercoagulable state indirectly.
It is suggested that the antibodies created in response to Mycoplasma
infection form immune complexes that cause an inflammatory response in
the pulmonary arteries, leading to endothelial damage and the subsequent
release of procoagulants.[8] In vitro experimental studies have
suggested that lipoglycans from some mycoplasmas can induce procoagulant
activity through the expression of tissue factors in human mononuclear
cells, leading to increased procoagulant activity in these
patients.[10] M. pneumoniae infection can lead to transient
elevation of antiphospholipid antibodies, which is commonly seen in
systemic lupus erythematosus and is associated with an increased risk of
both arterial and venous thrombosis.[11] Additionally, some
physiological coagulation inhibitors, including protein C system and
tissue factor pathway inhibitors, may be impaired.[2]
Autoimmune hemolytic anemia (AIHA) is a disorder characterized by
autoantibody-mediated hemolysis. Cold agglutinin disease (CAD) is a form
of complement-mediated AIHA, in which the pathophysiology is driven by
IgM autoantibodies binding to the I antigen on the surface of red blood
cells (RBCs) at or just below the core body temperature.[1, 4, 12,
13] The I antigen is contained in long-chain sialo-oligosaccharides,
which serve as receptors for M. pneumoniae. Cold agglutinins are IgM
antibodies directed against I antigens.[14] 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. The majority of opsonin-coated
RBCs are removed from circulation by the mononuclear phagocyte system,
resulting in extravascular hemolysis. Classical pathway activation may
proceed to the terminal portion of the complement pathway on some RBC
membranes, resulting in the formation of a membrane attack complex
(C5b-9) and intravascular hemolysis.[4] Hemolytic anemia associated
with multiple vascular thromboses is a rare but severe complication of
M. pneumoniae.[9] Thrombosis in autoimmune hemolytic anemia 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.[15] Agglutination of RBCs also
increases blood viscosity , causing reduced blood flow and stasis, which
may contribute to the gradual formation of venous thrombosis.[12]
Therefore, when the cold agglutinin antibody titer is high, attention
should be paid to the possibility of autoimmune hemolysis and
thrombosis.
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.[16] Despite improvements in ECMO technology, bleeding and
thrombosis remain significant complications as the interaction between
the patient’s native blood and the foreign surface of the ECMO circuit
activates the coagulation cascade.[17] We use continuous
unfractionated heparin infusion (5–20 U/kg/h) for the anticoagulation
protocol. The target ACT range was 180–200 s to monitor
anticoagulation.
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,[18] 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.
The American Society of Hematology guideline panel recommends using
anticoagulants in pediatric patients with symptomatic deep vein
thrombosis or pulmonary embolism when hemodynamics are stable.
Thrombolysis followed by anticoagulation is recommended for pediatric
patients with pulmonary embolism and hemodynamic compromise.[19]
After ECMO treatment, pulmonary embolism was confirmed, the hemodynamics
of the child were stable; thus, low-molecular-weight heparin was
continued for anticoagulant therapy, and the pulmonary embolism
gradually disappeared after the follow-up. If the diagnosis of pulmonary
embolism was confirmed earlier and thrombolytic drugs actively used, our
patient could have avoided uncorrectable hypoxemia and ECMO treatment.
There were some limitations in our case study. Inherited thrombophilia
(IT) is strongly associated with venous thromboembolism. IT, including
factor V Leiden mutation, prothrombin G20210A mutation, antithrombin
deficiency, protein C deficiency, and protein S deficiency were not
tested in our patient. However, the impact of these disorders on
thromboembolism development in children remains poorly defined and
controversial.
In summary, M. pneumoniae is a common community-acquired pathogen. A
diagnosis of pulmonary embolism could easily be missed in a patient with
pneumonia, whose symptoms of chest pain, shortness of breath, and
pleural effusion could easily be attributed to pneumonia. In addition,
some patients may be asymptomatic. 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.
Cases of M. pneumoniae infection leading to subclinical thrombi are
likely to be higher than reported, and more sensitive means of
examination are yet to be explored. Moreover, whether magnetic resonance
imaging provides new evidence for these pathological changes remains
under study. 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.
Acknowledgements
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