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\begin{document}

\title{Late diagnosis of X-linked hyper-IgM syndrome presenting as
community-acquired pseudomonas aeruginosa pneumonia-related septic shock}



\author[1]{Lin Yang}%
\author[1]{Lina Chen}%
\author[1]{Liang Xie}%
\author[1]{Ying Xiong}%
\author[1]{Hanmin Liu}%
\affil[1]{Sichuan University West China Second University Hospital}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative aerobic
bacterium, which is rarely seen in community-acquired infection.
Attention should be paid to its high mortality and invasive progress.
X-linked hyper-IgM syndrome (XHIGM; HIGM1; OMIM:308230) is one type of
primary immunodeficiency disease (PIDs), characterized by markedly
decreased serum IgG, IgA, and IgE levels and normal or elevated serum
IgM levels. We report a patient who developed a particularly severe
community-acquired P. aeruginosa pneumonia-related septic shock, and a
delayed diagnosis of X-linked hyper IgM syndrome was made by genome
sequencing. Fatal community-acquired P. aeruginosa infections in
children, including previously healthy children, should be considered to
search for underlying PIDs by exome/genome sequencing.%
\end{abstract}%



\sloppy


\textbf{Title page}

\textbf{Late diagnosis of X-linked hyper-IgM syndrome presenting as
community-acquired pseudomonas aeruginosa pneumonia-related septic
shock}

Lin Yang, E-mail:\emph{linyang821@163.com}

Lina Chen, E-mail:chenlina\_78@163.com

Liang Xie, E-mail:xeronxie@163.com

1. Department of Pediatric Pulmonology and Immunology, West China Second
University Hospital, Sichuan University, Chengdu, China.

2. Key Laboratory of Birth Defects and Related Diseases of Women and
Children (Sichuan University), Ministry of Education, Chengdu, China.

3. NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu,
China.

4. The Joint Laboratory for Lung Development and Related Diseases of
West China Second University Hospital,Sichuan University and School of
Life Sciences of Fudan University, West China Institute of Women and
Children's Health, West China Second University Hospital, Sichuan
University, Chengdu, China

\textbf{*Corresponding author:}

Ying Xiong, E-mail: xiongying246@163.com

1. Department of Pediatric Pulmonology and Immunology, West China Second
University Hospital, Sichuan University, Chengdu, China.

2. Key Laboratory of Birth Defects and Related Diseases of Women and
Children (Sichuan University), Ministry of Education, Chengdu, China.

3. NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu,
China.

Hanmin Liu, E-mail:\emph{liuhm@scu.edu.cn}.

1. Department of Pediatric Pulmonology and Immunology, West China Second
University Hospital, Sichuan University, Chengdu, China;

2. Key Laboratory of Birth Defects and Related Diseases of Women and
Children (Sichuan University), Ministry of Education, Chengdu, China;

3. NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu,
China;

4. The Joint Laboratory for Lung Development and Related Diseases of
West China Second University Hospital,Sichuan University and School of
Life Sciences of Fudan University, West China Institute of Women and
Children's Health, West China Second University Hospital, Sichuan
University, Chengdu, China

5. Sichuan Birth Defects Clinical Research Center,West China Second
University Hospital, Sichuan University, Chengdu, China

\textbf{Conflict of interests}

The authors declare that there is no conflicts of interest.

\textbf{Author contributions}

Lin Yang: data collection; writing original draft; writing review and
editing. Lina Chen and Liang Xie: data collection and manuscript
revision. Ying Xiong and Hanmin Liu: study concept and design,
interpretation of results, manuscript, revision, and final approval. All
authors contributed to the article and approved the submitted version.

\textbf{Running head:}

\textbf{Late diagnosis of X-linked hyper-IgM syndrome by exome/genome
sequencing}

\textbf{Keywords:} Pseudomonas aeruginosa, community-acquired infection,
X-linked hyper-IgM syndrome, PIDs, exome/genome sequencing



\textbf{Abstract}

Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative aerobic
bacterium, which is rarely seen in community-acquired infection.
Attention should be paid to its high mortality and invasive progress.
X-linked hyper-IgM syndrome (XHIGM; HIGM1; OMIM:308230) is one type of
primary immunodeficiency disease (PIDs), characterized by markedly
decreased serum IgG, IgA, and IgE levels and normal or elevated serum
IgM levels. We report a patient who developed a particularly severe
community-acquired P. aeruginosa pneumonia-related septic shock, and a
delayed diagnosis of X-linked hyper IgM syndrome was made by genome
sequencing. Fatal community-acquired P. aeruginosa infections in
children, including previously healthy children, should be considered to
search for underlying PIDs by exome/genome sequencing.

\textbf{Introduction}

\emph{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
infections\textsuperscript{1}. According to some cases
\textsuperscript{2,3}, community-acquired \emph{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
\textsuperscript{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 \textsuperscript{5}. We report a patient who developed a
particularly severe community-acquired \emph{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 \emph{P.
aeruginosa} infection.

\textbf{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 \selectlanguage{ngerman}°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 0.2\selectlanguage{greek}μ\selectlanguage{english}g/kg/min, HR 160 bpm, RR
60 bpm, temperature 38.9\selectlanguage{ngerman}°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\(\times\)10\textsuperscript{9}/l, neutropenia of
0.07\(\times\)10\textsuperscript{9}/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 \textless{}17),
serum aspartate aminotransferase 102IU/L (N \textless{}40), serum
alanine aminotransferase 59 IU/L(N \textless{}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 \emph{P.
aeruginosa}two days after admission (Table 1). Second-generation
sequencing of blood and sputum samples also showed quantities of
\emph{P. aeruginosa}duplication (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\textgreater{}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.

\textbf{Discussion}

\emph{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
enzymes\textsuperscript{5}. 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 \textsuperscript{1}. The
typical patient presenting with nosocomial \emph{P. aeruginosa}infection
is mechanically ventilated, has slowly progressive lung infiltrates, and
has been colonized for days \textsuperscript{6}. Community-acquired
\emph{P. aeruginosa} infections are rare but have an acute onset, rapid
progression, and lead to the development of short-term shock
\textsuperscript{7,8}. The patient in our study diagnosed severe
community-acquired pneumonia (CAP) due to \emph{P. aeruginosa} and also
progressed to septic shock quickly.

In CAP, \emph{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
admission\textsuperscript{1}. In severe \emph{P. aeruginosa} CAP (PCAP),
mortality of those who developed progressive septic shock and MODS can
reach as high as 50--100\% \textsuperscript{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 \textsuperscript{11} and
require different antibiotic therapy \textsuperscript{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, \emph{P. aeruginosa} infection should be considered in
patients with severe rapidly progressive pneumonia \textsuperscript{6}.

The resistance of community-acquired \emph{P. aeruginosa} isolates to
many commonly used anti-pseudomonal antibiotics remains extremely low,
unlike the extended resistance patterns often seen in
nosocomial\textsuperscript{13,14}. In most clinical situations, the
treatment of choice for a \selectlanguage{greek}β-\selectlanguage{english}lactam susceptible \emph{P. aeruginosa}
infection is \selectlanguage{greek}β-\selectlanguage{english}lactam monotherapy except in the following cases: 1)
during the first 72 hours if the infection presents criteria of severe
sepsis or septic shock \textsuperscript{1}, 2) in the neutropenic
patient\textsuperscript{15}, and 3) in central nervous system
(meningitis, abscess) or endovascular (endocarditis) infections
\textsuperscript{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 \emph{P. aeruginosa} pneumonia
\textsuperscript{17-19}. For critically ill patients admitted to the
ICU, guidelines recommend an antipseudomonal \selectlanguage{greek}β-\selectlanguage{english}lactam
(piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus an
antipseudomonal fluoroquinolone; or the above \selectlanguage{greek}β-\selectlanguage{english}lactam plus an
aminoglycoside and azithromycin; or the above \selectlanguage{greek}β-\selectlanguage{english}lactam plus an
aminoglycoside and a fluoroquinolone. Once \emph{P. aeruginosa} is
suspected or confirmed to be the pathogenic agent, the antibiotic
regimen should be adjusted to be more targeted. An antipseudomonal
\selectlanguage{greek}β-\selectlanguage{english}lactam plus an aminoglycoside or a fluoroquinolone, with the
alternative being an aminoglycoside plus a fluoroquinolone was
recommended \textsuperscript{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 \textsuperscript{15}. Despite severe pneumonia with
shock, bronchiectasis and severe neutropenia, we ignored the possibility
of \emph{P. aeruginosa} infection.

Community-acquired \emph{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 children\textsuperscript{5}. 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 \emph{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\textgreater{}C (p.q174R) mutation in the CD40LG
gene. Hyper-IgM (HIGM) syndrome (24.1\%) is one of the main PIDs in
China \textsuperscript{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
age\textsuperscript{22}. 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
bronchiectasis\textsuperscript{23}. In a previous report, 68\% of XHIGM
patients had neutropenia and 45\% were chronic. If neutropenia is
severe, it may respond to G-CSF \textsuperscript{24}. The use of
trimethoprim-sulfamethoxazole for prophylaxis of PJP may also be
beneficial \textsuperscript{25}. Bone marrow transplantation performed
early in life may cure XHIGM \textsuperscript{22}. Congenital disorders,
such as immunodeficiencies and ciliary defects, were
included\textsuperscript{26}.

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 \textsuperscript{5}. As the cost
of genome sequencing is reduced, molecular diagnosis can be made earlier
to offer definitive management \textsuperscript{27}.

In conclusion, \emph{P. aeruginosa} is an uncommon but fatal causative
pathogen for community-acquired infections. Empirical antibiotics
treatment should cover \emph{P. aeruginosa} in patients with rapidly
progressive disorders. Fatal community-acquired \emph{P.
aeruginosa}infections in children, including previously healthy
children, should be considered to search for underlying PIDs by
exome/genome sequencing.

\textbf{Funding}

This study was supported by the National Natural Science Foundation of
China Joint Fund for Regional Innovation and Development (U21A20333),
the Fundamental Research Funds for the Central
Universities(SCU2022D022)and the grant 22ZDZX0014 and 2020YFS0105 from
the Science \& Technology department of Sichuan Province.

\textbf{Acknowledgments}

None.

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