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\begin{document}

\title{Hypersensitivity pneumonitis associated with the yeasts Trichosporon
asahii and Candida parapsilosis and with humidifier fever.}



\author[1]{Dianguina Soumare}%
\author[1]{Tenin Kanoute}%
\author[1]{Lucie Cassagnes}%
\author[1]{Guillaume Laurichesse}%
\author[1]{Daniela Muti}%
\author[1]{Denis Caillaud}%
\affil[1]{Clermont Auvergne University}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
Here, we present the first case of hypersensitivity pneumonitis to
Yeasts (Trichosporon asahii and Candida parapsilosis) and associated
with humidifier fever linked to exposure to gram negative bacteria and
endotoxins. The association of HP and humidifier fever is rarely
reported.%
\end{abstract}%



\sloppy


\textbf{Hypersensitivity pneumonitis associated with the
yeasts\emph{Trichosporon} \emph{asahii} and \emph{Candida parapsilosis}
and with humidifier fever.}

Dianguina Soumare \textsuperscript{1}, Tenin Kanoute\textsuperscript{1},
Cassagnes L\textsuperscript{2}, Guillaume Laurichesse
\textsuperscript{1}, Daniela Muti \textsuperscript{1}, Denis Caillaud
\textsuperscript{1}.

1 Service de Pneumologie-Allergologie, CHU Gabriel Montpied, Clermont
Auvergne University, 63003 Clermont-Ferrand, France;

2. Service de Radiologie, CHU Gabriel Montpied, Clermont Auvergne
University, 63003 Clermont-Ferrand, France

\emph{Corresponding Author} : Denis Caillaud, G Montpied Hospital,
Montalembert Street, 63003 Clermont-Ferrand, France. Tel: 33 4 73751653
Fax: 33 4 73751656 Email:\emph{dcaillaud@chu-clermontferrand.fr}

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy

\emph{Abstract}

Here, we present the first case of hypersensitivity pneumonitis to
Yeasts (\emph{Trichosporon asahii} and \emph{Candida parapsilosis)} and
associated with humidifier fever linked to exposure to gram negative
bacteria and endotoxins.

The association of HP and humidifier fever is rarely reported.

\textbf{Key clinical message:} Anamnesis should explore the use of a
humidifier in the case of fever or any HP with an undetermined cause,
and test for germs in the humidifier. The most important treatment is to
cease using a humidifier.

\textbf{Keywords:} \emph{Candida;} Endotoxins; Extrinsic allergic
alveolitis; Humidifier fever; Hypersensitivity pneumonitis\emph{;
Trichosporon} \emph{asahii} .

INTRODUCTION

Hypersensitivity pneumonitis (HP) is a lung disease caused by
significant and recurrent inhalation of antigens. Diagnostic criteria
are based on antigen exposure, clinical signs, lowered diffusing
capacity for carbon monoxide (DL\textsubscript{CO}), imaging (ground
glass, centrilobular nodules, air trapping identified on expiratory
high-resolution computed tomography), and compatible bronchoalveolar
lavage (lymphocytosis and mastocytosis), whether or not associated with
the presence of immunoglobulin G (IgG) precipitins {[}1, 2{]}. Its
annual incidence is estimated to be about 0.9 to 2 cases per 100,000
population {[}3-5{]}. The main etiologies are farmer's lung, bird
breeder's lung, and domestic HP {[}6{]}.

In contrast, respiratory pathologies associated with humidifier use
(humidifier-HP and humidifier fever) are rare {[}7{]}. The first known
cases of humidifier-HP involved warm-water humidifiers, and were
associated with thermophilic actinomycetes; subsequent cases involving
ultrasonic cold-water humidifiers revealed different pathogens, such as
molds or bacteria {[}8{]}. Humidifier fever is rarely reported in the
literature {[}9-11{]} and represents a diagnostic challenge for the
physician. Repeated febrile episodes, associated with hyperleucocytosis
and increased C-reactive protein (CRP), should lead to the suspicion of
exposure to endotoxins, classically reported in farmers, particularly in
the form of organic dust toxic syndrome {[}12{]}, or experimentally
after inhalation of endotoxins in humans {[}13{]}. Gram negative
bacteria containing endotoxins have been detected in humidifier fever
(HF) in Japan {[}9{]} and Germany {[}10, 11{]}. However, associations
between HP and humidifier fever have been rarely reported {[}14{]}.

We present here a rare case of HP associated with yeasts
(\emph{Trichosporon asahii} and \emph{Candida parapsilosis)} , and with
humidifier fever (exposition to Gram negative bacteria and endotoxins).

CASE PRESENTATION

A retired 63-year-old woman was admitted to the pulmonary department on
January 2020 for progressive dyspnea on exertion over the previous 15
days. She had a history of allergic asthma (dust mites, cats, pollens)
since childhood, treated with inhaled long-acting beta2-agonists and
corticosteroids. She was a former smoker (20 pack-year) who had ceased
15 years prior to presentation. Within her home, no birds, mould or
humidity were present. Intermittent febrile episodes at 38-38.5\selectlanguage{ngerman}°C had
occurred over the previous 9 months. Eight months before admission, a
blood count recorded leukocytosis of 10,200 G/L (ref. range 4-10 G/L),
neutrophils at 7,049 G/L (ref. range 1.5-7 G/L) and CRP at 20.8 mg/l.
Two weeks prior to admission, the white blood cell count had risen to
10,550 G/L, neutrophils to 7,611 G/L and CRP at 73.1 mg/L. Twenty-four
hours before hospitalization, the white blood cell count was 13,100 G/L,
neutrophils 10,860 G/L and CRP 25.2 mg/l. Multiple lines of antibiotics
including amoxicillin and ceftriaxone had not resulted in any
improvement in febrile episodes.

Clinical examination revealed a dyspneic patient with a preserved
general condition. Her temperature was 37°C, and peak expiratory flow
was 320 L/min (normal value 420). A physical examination revealed some
fine crackles at the bases.

An arterial blood gas test performed on admission recorded hypoxia at 56
mm Hg. The chest X-ray was normal. Inspiratory injected high resolution
computed tomography was normal, without any pulmonary embolism. However,
mild trapping was present on expiratory images (Fig.1). Laboratory
studies revealed leukocytosis at 10,800G/L with CRP at 10 mg/l;
D-dimers, pro-BNP and procalcitonin were normal. Antinuclear antibodies,
connective tissue antibodies, anti-neutrophil cytoplasm antibodies,
brucellosis, typhoid fever, Coxiella serology, and sputum smear tests
were all negative, while cardiac ultrasound ruled out endocarditis.
Pulmonary function tests performed two days after admission revealed
lowered TLCO (72\% of predicted), small-airway bronchial obstruction
(FEF 25-75 28\% of predicted), and no decrease in lung volumes (total
lung capacity (TLC) at 111\%, FVC at 106\%). Six days post-admission, a
broncho-alveolar lavage performed after bronchodilator aerosol
application revealed hyper-cellularity, with 467,000 cells/ml (100,000
and 150,000 cells/ml in a non-smoker is normal), with
hyper-lymphocytosis at 32\%, neutrophilia at 10\% and mast cells at 1\%.
The tests for viruses, bacteria and mycobacteria were
negative.\emph{Aspergillus. fumigatus, Micropolyspora faeni} and pigeon
breeder's serologies were negative. Lung biopsy was not possible due to
hypoxia.

Faced with these repeated febrile and respiratory episodes suggestive of
acute hypersensitivity pneumonitis, along with the association with
hyperleukocytosis and increased CRP, the consequent search for an
environmental origin revealed the daily use of an ultrasonic humidifier
in the home for about 2 years (Fig. 2). Over time, the patient had
refilled the water when needed, but without cleaning the water
reservoir. Bacteriological and mycological analysis of the humidifier
water tank found colonies of \emph{T. asahii} and \emph{C.
parapsilosis}and the presence of \emph{Enterobacter} \emph{cloacae}
and\emph{Acinetobacter} sp. Precipitins (electrosyneresis) were positive
with 2 arcs for \emph{T asahii} and \emph{C. parapsilosis} . Endotoxins
in the humidifier water were at 3900 Endotoxin Units (EU)/ml
(quantitative limulus assay)

The patient received oral corticotherapy (60 mg prednisone/24H
{[}1mg/kg{]}), from the day of admission because she had difficulty
breathing (especially at night). This resulted in a rapid improvement in
her respiratory condition. She returned home after one week's
hospitalization with decreasing corticosteroid doses, and she removed
the humidifier from the house. The patient rapidly recovered from the
clinical symptoms, with the disappearance of dyspnea and no recurrence
of febrile episodes. One month later, recovery of pulmonary function was
observed with TLC at 129\% of predicted, FVC at 120\%,
FEV\textsubscript{1} at 100\%, and post-BD FEV\textsubscript{1}/FVC at
70\%, but with a continuing mild diffusion disorder
(DL\textsubscript{CO} 79\% of predicted).

\emph{Discussion} :

Given the risk of a severe attack (the patient was hypoxic on arrival at
the hospital), and due to the lack of standardization (mixture of
non-specific antigens and non-specific irritants), a provocation test
was not performed on this patient. The diagnosis of HP is nevertheless
certain because of the diagnostic criteria present in this patient:
exposure to antigens (yeasts and bacteria within the humidifier),
positive precipitins to yeasts, significant lymphocytosis on BAL with
mastocytosis, crackles on auscultation and a decreased DLCO. An isolated
air trapping on the HRCT is a pattern that may be seen with HP {[}1{]}.
The absence of expiratory wheezing counted against a diagnosis of
asthma, and crepitants are not present in this disease except in heart
failure (however pro-BNP was normal).

This case of humidifier-HP resulted from yeasts (\emph{Trichosporon.
asahii} and \emph{Candida. parapsilosis} colonies in the humidifier
water tank, and positive yeast IgG precipitins identified by
electrosyneresis). Evidence for HF was also found; intermittent febrile
episodes, with hyperleukocytosis and neutrophilia, increased CRP, and
evidence of gram-negative bacteria in the water tank, along with
endotoxins. The diagnosis was confirmed by the patient's clinical
improvement after she stopped using the humidifier at home. The recovery
of DL\textsubscript{CO} was slower (79\% of predicted) than of FVC, in
accordance with what is observed in the follow-up study of pulmonary
function in farmer's lung {[}15{]}. With post-bronchodilator FEV1/FVC at
70\%, the final obstructive lung disease diagnosis in this patient was
asthma rather than asthma-COPD-overlap (ACO) {[}16{]}.

No case of hypersensitivity pneumonitis with the detection of \emph{T.
asahii} in a humidifier has been described to our knowledge. This yeast
is classically found in acute {[}17{]} or chronic {[}18{]} summer-type
HP (the most frequent HP in Japan), which usually occurs during the hot
and humid summer period after exposure to mould in wooden houses. It is
due to exposure to \emph{T. asahii} or \emph{T.}
\emph{mucoides}(formerly \emph{T.} \emph{cutaneum} ) {[}19{]}. Three
cases of humidifier-related HP have been described after contamination
with\emph{Candida albicans} {[}20, 21{]} or \emph{Candidaguilliermondii}
{[}22{]} but none associated with \emph{Candida paraspsilosis.}

Humidifier fever is associated with gram-negative bacteria, which
contain endotoxins. Bacteria found in our observations
(\emph{Enterobacter} \emph{cloacae} , \emph{Acinetobacter} sp.) were
also reported in publications in Japan {[}9{]}, Germany {[}14{]} and USA
{[}23{]}. The high level of endotoxins found in the humidifier (the
typical level in tap water is 25 EU/ml {[}24{]}) may have exacerbated
the hypersensitivity allergic reaction, as shown in animal {[}25{]} and
clinical studies {[}26{]}.

Conclusion

We report a rare case of humidifier-HP associated with yeasts
(\emph{Trichosporon asahii} and \emph{Candida parapsilosis)} . The
association of humidifier-HP and humidifier fever is exceptionally
reported. In any case of hypersensitivity pneumonitis with an
unidentified cause, the use of a humidifier should be systematically
investigated.

\textbf{The authors declare that they have no conflict of interest
(COI).}

\emph{Acknowledgment: a written informed consent for publishing was
obtained from the patient}

Author contributions: DS, LC and DC were in charge of developing the
manuscript. TK, GL and DM participated to the manuscript discussion and
approval of the final version.

\textbf{Data avaibility statement:} Data sharing not applicable to this
article as no datasets were generated or analysed during the current
study.

\emph{}

\textbf{Figure legend:}

Figure 1: Mild trapping shown on expiration High Resolution Computed
Tomography, which is compatible with hypersensitivity pneumonitis.

Figure 2: Humidifier water tank: The humidifier tank was refilled with
water as needed, but without prior cleaning. This resulted in bacterial
and mycological contamination of the tank.

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