Introduction
Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative aerobic
bacterium, one of the major pathogenic bacteria in hospital-acquired
infection. It is rarely seen in community-acquired infections1. According to some cases 2,3,
community-acquired P. aeruginosa may cause severe aggressive
infections in healthy children. 25% of fatal cases were found to carry
novel pathogenic variants in PID genes by exome/genome sequencing in
previously healthy children 4. X-linked hyper-IgM
syndrome (XHIGM; HIGM1; OMIM:308230) is one type of primary
immunodeficiency disease(PIDs), resulting from defects in the CD40
ligand/CD40 signaling pathways leading to impairment of immunoglobulin
isotype switching in B cells. It was characterized by recurrent
infections in association with markedly decreased serum IgG, IgA, and
IgE levels but normal or elevated serum IgM levels 5.
We report a patient who developed a particularly severe
community-acquired P. aeruginosa pneumonia-related septic shock,
and late diagnosis of X-linked hyper IgM syndrome was made by genome
sequencing. Pediatricians should evaluate immune status in aggressive
cases of community-acquired P. aeruginosa infection.
Case presentation
A 15-year-old male patient with a 5-day history of fever and cough was
admitted to the pediatric intensive care unit (PICU) due to worsening
dyspnea and mental status over four hours. The patient had a positive
history of recurrent respiratory tract infections, 1-2 times per year,
while his siblings did not. The patient had never received prior
immunosuppressive drugs and had no previous history of malignancy. He
had no skin rashes and no tobacco or alcohol use. Parents were
nonconsanguineous and healthy without a history of contagious disease or
sick contacts. Five days before admission, the patient started having
fever and cough self-treated by unknown oral medications without
improvement. One day before admission, he felt chest pain and shortness
of breath. Intravenous antibiotics medications were given. Four hours
before admission, the patient deteriorated rapidly with chest tightness,
dyspnea, and cyanosis. The patient sent to a local healthcare facility.
The physical exam revealed the following: T 38.0 °C, BP 90/58 mmHg, HR
158 bpm, R 56 bpm, SpO2 89% with peripheral cyanosis and dyspnea. Chest
computed tomography (CT) showed an infection site in the right lung.
Facemask oxygen and fluid resuscitation were given, then the patient
transferred to our PICU with drowsiness, hypotension, and dyspnea.
Physical exam on PICU admission was as follows: BP 90/35mmHg with
intravenous infusion of norepinephrine of 0.2μg/kg/min, HR 160 bpm, RR
60 bpm, temperature 38.9°C, SpO2 89% with facemask oxygen. The Glasgow
coma scale was 10/15. Normal habitus, unconsciousness, breathlessness,
mottled skin without petechiae or necrosis, bilateral rough breath
sounds without rales or rhonchi, flat abdomen with mildly increased
tension, poor circulation with prolonged capillary filling time. Initial
blood investigations revealed a decrease in white cell count of
0.4\(\times\)109/l, neutropenia of
0.07\(\times\)109/l, and elevated C-reactive protein
levels (299.6mg/l). PCT was 21.75ng/ml. Arterial blood gas showed pH
7.28, PaCO2 4 mmHg, PaO2 87mmHg, lactate 7.1mmol/Land BE – 9.4mmol/L.
Serum creatinine 106mmol/l (N 35.9-83.1mmol/l), serum urea12mmol/L (N
3-8), serum bilirubin26.2 mmol/l (N <17), serum aspartate
aminotransferase 102IU/L (N <40), serum alanine
aminotransferase 59 IU/L(N <49). The HIV test was normal.
Cardiac ultrasound showed that the left ventricular ejection fraction
(LVEF) was 55% and normal cardiac structure. Chest CT showed multiple
nodular, patchy shadows and bronchiectasis in the bilateral lung, while
abdominal and pelvic CT scans were unremarkable.
He was intubated immediately and mechanical ventilation started.
According to early goal-directed therapy (EGDT), adequate fluid
resuscitation and norepinephrine were given. Blood and sputum samples
were collected at first and sent for microbiology tests.
Second-generation sequencing of blood and sputum samples were sent at
the same time. Then empiric antibiotics treatment with imipenem and
linezolid initiated. Continuous renal replacement therapy (CRRT) started
due to AKI state 2 and high lactate level. Based on hemodynamic
monitoring, vasoactive agents and fluid resuscitation with volume and
rate were adjusted. The patient was worsening rapidly with persistent
hypotension. Numerous aggressive hemodynamic resuscitation attempts and
symptomatic treatment could not stop the rapidly fatal pathological
process. The patient died due to septic shock 11 hours after admission.
Both blood and sputum cultures indicated growth of P. aeruginosatwo days after admission (Table 1). Second-generation sequencing of
blood and sputum samples also showed quantities of P. aeruginosaduplication (Table 2). The patient in our study started with cough
companying with chest pain, chest tightness, dyspnea and fatigue. Chest
CT showed multiple nodular, patchy shadows and bronchiectasis.
Community-acquired Pseudomonas aeruginosa pneumonia-related septic shock
confirmed. The rare invasive progress and the history of recurrent
bronchitis since 6 months raised our suspicion of underlying
immunodeficiencies. Genome sequencing was made and later identified a
c.512A>C (p.q174R) mutation in the CD40LG gene, and the
diagnosis of XHIGM ultimately confirmed. The parents’ genetic tests were
not done for economic reasons. Written informed consent was obtained to
publish this case report and any accompanying images.
Discussion
Pseudomonas aeruginosa, (P. aeruginosa) is an aerobic
Gram-negative bacterium commonly found in the environment and has strong
virulence, producing various toxins, including exotoxins and enzymes5. This opportunistic pathogen is an important cause
of nosocomial infections and community-acquired infections in
immunocompromised patients and patients with structural lung disease,
such as bronchiectasis and cystic fibrosis 1. The
typical patient presenting with nosocomial P. aeruginosainfection is mechanically ventilated, has slowly progressive lung
infiltrates, and has been colonized for days 6.
Community-acquired P. aeruginosa infections are rare but have an
acute onset, rapid progression, and lead to the development of
short-term shock 7,8. The patient in our study
diagnosed severe community-acquired pneumonia (CAP) due to P.
aeruginosa and also progressed to septic shock quickly.
In CAP, P. aeruginosa is rarely identified as the pathogenic
agent, accounting for only 0.4–6.9% in reported cases of CAP requiring
hospitalization and 1.8–8.3% of CAP requiring ICU admission1. In severe P. aeruginosa CAP (PCAP),
mortality of those who developed progressive septic shock and MODS can
reach as high as 50–100% 9,10. The common
manifestations of PCAP are fever, cough and chest pain, usually
involving the right upper lobe. Ecthyma gangrenosum is also a known
cutaneous manifestation. Compared to typical CAP, PCAPs are inclined to
have respiratory failure and septic shock 11 and
require different antibiotic therapy 12. The 2007
American Thoracic Society (ATS) / Infectious Diseases Society of America
(IDSA) guidelines recommended empirical treatment against P. aeruginosa
in community-acquired pneumonia (CAP) patients with the following
specific risk factors: 1) structural lung disease, like bronchi, 2)
recurrent exacerbations of COPD requiring corticosteroid/antibiotic
treatment, 3) antibiotic use before admission,4)immunocompromised
status. Besides, P. aeruginosa infection should be considered in
patients with severe rapidly progressive pneumonia 6.
The resistance of community-acquired P. aeruginosa isolates to
many commonly used anti-pseudomonal antibiotics remains extremely low,
unlike the extended resistance patterns often seen in nosocomial13,14. In most clinical situations, the treatment of
choice for a β-lactam susceptible P. aeruginosa infection is
β-lactam monotherapy except in the following cases: 1) during the first
72 hours if the infection presents criteria of severe sepsis or septic
shock 1, 2) in the neutropenic patient15, and 3) in central nervous system (meningitis,
abscess) or endovascular (endocarditis) infections 16.
Combination therapy with appropriate anti-Pseudomonas agents must be
instituted immediately on presentation (within one hour) to prevent the
emergence of resistance and improve the prognosis of fulminant P.
aeruginosa pneumonia 17-19. For critically ill
patients admitted to the ICU, guidelines recommend an antipseudomonal
β-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem)
plus an antipseudomonal fluoroquinolone; or the above β-lactam plus an
aminoglycoside and azithromycin; or the above β-lactam plus an
aminoglycoside and a fluoroquinolone. Once P. aeruginosa is
suspected or confirmed to be the pathogenic agent, the antibiotic
regimen should be adjusted to be more targeted. An antipseudomonal
β-lactam plus an aminoglycoside or a fluoroquinolone, with the
alternative being an aminoglycoside plus a fluoroquinolone was
recommended 20. Carbapenems have been administered as
a second-line empirical antibiotic agent for patients with persistent
fever despite the first-line empirical antibiotic therapy until
neutropenia recovery 15. Despite severe pneumonia with
shock, bronchiectasis and severe neutropenia, we ignored the possibility
of P. aeruginosa infection.
Community-acquired P. aeruginosa may cause severe aggressive
infections in healthy children. 25% of fatal cases found novel
pathogenic variants in PID genes by exome/genome sequencing in
previously healthy children5. PIDs refer to a
heterogeneous group of over 130 disorders that result from defects in
immune system development and/or function. It is characterized by
diverse clinical manifestations, such as recurrent or prolonged serious
infections, autoimmune/inflammatory disease, allergy, or malignancy.
Community-acquired P. aeruginosa pneumonia-related septic shock
was unusual in our patient’s age group and later raised the suspicion of
immunodeficiencies. The diagnosis of XHIGM was ultimately confirmed
genetically for a c.512A>C (p.q174R) mutation in the CD40LG
gene. Hyper-IgM (HIGM) syndrome (24.1%) is one of the main PIDs in
China 21. CD40L and CD40 mutations have been
classified into combined T and B immunodeficiency. Patients with XHIGM
usually develop symptoms by the first or second year of life. Only 20%
of patients with XHIGM survive beyond 25 years of age22. Therapy for HIGM is monthly infusions of IVIG that
reduce the frequency and severity of infections. However, IVIG did not
prevent the development of sclerosing cholangitis or bronchiectasis23. In a previous report, 68% of XHIGM patients had
neutropenia and 45% were chronic. If neutropenia is severe, it may
respond to G-CSF 24. The use of
trimethoprim-sulfamethoxazole for prophylaxis of PJP may also be
beneficial 25. Bone marrow transplantation performed
early in life may cure XHIGM 22. Congenital disorders,
such as immunodeficiencies and ciliary defects, were included26.
Despite typical clinical manifestations or features, underlying PIDs may
still be ignored. Late diagnoses or misdiagnosis are common. Reaching
definitive pathogeny is vital for better management of any clinical
case. Failure to diagnose underlying PIDs in a child may result in
potentially devastating consequences for survivors, undiagnosed
siblings, and their families. Genome sequencing, in particular
high-throughput or exome sequencing, successfully diagnosed monogenic
conditions in the pediatric population 5. As the cost
of genome sequencing is reduced, molecular diagnosis can be made earlier
to offer definitive management 27.
In conclusion, P. aeruginosa is an uncommon but fatal causative
pathogen for community-acquired infections. Empirical antibiotics
treatment should cover P. aeruginosa in patients with rapidly
progressive disorders. Fatal community-acquired P. aeruginosainfections in children, including previously healthy children, should be
considered to search for underlying PIDs by exome/genome sequencing.