Abstract
Newborn screening (NBS) of cystic fibrosis (CF) is not available
currently in Hungary. Pediatricians should be able to recognize the
illness based on the symptoms alone. Lack of NBS causes differential
diagnostic challenges for physicians and delayed diagnosis of CF. We
present a case of a two-year-old girl who was transferred to our
hospital as a suspected Covid-19 patient with one week history of fever
and coughing in March 2020. As Covid-19 was excluded, the severity of
the clinical picture pointed towards an acute exacerbation of an
underlying chronic condition. Her symptoms such as tachypnea, wheezing,
lung crackles, hepatomegaly and clubbing of the fingers were all
consistent with undiagnosed CF. In the end, sweat chloride level and
genetic test verified the diagnosis. This case emphasizes the need of
NBS in Hungary.
Keywords: Covid-19, cystic fibrosis, newborn screening
Introduction
A cluster of cases of pneumonia were reported in Wuhan, China in
December 2019. In January 2020 the genetic sequence of the novel corona
virus was detected and in March the World Health Organization (WHO)
characterized Covid-19 as a pandemic. Heim Pál Children’s Hospital was
assigned to hospitalize suspected or verified SARS-CoV-2 infected
children in Central Hungary on 21st March.
Case
A two-year-old girl was admitted to our hospital with a suspected
diagnosis of SARS-CoV-2 pneumonia in March 2020. She presented in
infancy with chronic cough, frequent respiratory illnesses, and failure
to thrive (BMI 3rd percentile, Z score = -1,99).
In March 2020 she was admitted to the local hospital, in Eastern Hungary
with fever, difficulty of breathing and one week history of coughing.
Due to her respiratory symptoms a SARS-CoV-2 PCR test was carried out on
the 7th day of her illness. The result of the PCR test
was unclear therefore she was transferred to our hospital. On arrival
tachypnea, wheezing, lung crackles, hepatomegaly, clubbing of the
fingers were found during the physical examination. It was also noticed
that her weight was under the 3rd percentile. Her
saturation was 95% on 3 l/min oxygen flow via the nebulizing mask.
Laboratory evaluation showed high white blood cell count with
neutrophilia. Shortly after admission her work of breathing
significantly increased, therefore high flow nasal cannula (HFNC) oxygen
therapy was implemented. Despite the frequent use of bronchodilators and
steroids wheezing did not improve. On the 10th day of
her illness nasopharyngeal swab for SARS-CoV-2 was reported to be
positive by our hospital.
The result was a surprise as the case did not fulfill the environmental
criteria of Covid-19 infection. First of all, the girl came from the
rural part of Eastern Hungary where the number of confirmed Covid-19
cases was extremely low, and second of all, no one in the family was
confirmed to be positive either. In addition to that, the severity of
symptoms and her past medical history brought up the possibility of an
undiagnosed underlying chronic condition. At that time, no false
positive SARS-CoV-2 PCR result was reported in the literature, therefore
we repeated the tests. Further testing, real time PCR nasopharyngeal
swab tests and serology tests were all found to be negative therefore we
excluded the diagnosis of Covid-19. According to our recent knowledge,
above 34 replication cycles no positive viral culture is obtained. (1)
Our explanation for the initial positive test could have come from the
fact that our laboratory repeated the PCR replication above 34 cycles
and nonspecific signals were misinterpreted positive.
On day 10 after admission, she was transferred to the Pediatric
Intensive Care unit for invasive ventilation due to further respiratory
distress on HFNC. All together, she required 10 days of mechanical
ventilation. Due to the worsening clinical picture, high resolution
computed tomography (HRCT) was performed, which revealed bronchial wall
thickening, mucus plugging and bronchiectasis consistent with CF
(Figure). Pseudomonas aeruginosa and methicillin-sensitive
Staphylococcus aureus (MSSA) was isolated from sputum, therefore
piperacillin-tazobactam (100 mg/kg/piperacillin four times a day) and
aminoglycoside (20 mg/kg/day once a day) were applied. After extubation,
she needed further 10 days of non-invasive ventilation before she was
finally stepped down to the General Pediatric ward.
Later on sweat chloride test (112 mmol/l) confirmed the diagnosis of
cystic fibrosis (CF), and a genetic test revealed a F508 del and G542X
mutation. The patient was started on regular pancreatic enzyme
replacement therapy, fat-soluble vitamins and nebulised colistimethate
sodium. She was also assessed by multidisciplinary CF team and was
started on regular physiotherapy. The CF-specific therapy led to a
better physical condition, but the consequences of the delayed diagnosis
and treatment are unknown at this stage.
Discussion
The Covid-19 pandemic in Hungary was started in the beginning of March.
Children are mostly reported to have milder symptoms or are
asymptomatic. The cause of the milder form of the disease is
hypothesized due to the high exposure of other viruses and the low
expression of ACE2 receptors. (2)
In 2018 in Hungary, there was a total of 523 patients with CF (age at
diagnosis 2.65 years) out of 9.7 million inhabitants. Unfortunately the
number of phenotyping, the average FEV1% and the BMI z-score lag far
behind the European average and the age of time at lung transplantation
is lower.
In Europe there are many different CF NBS protocols. All current
protocols rely on immunoreactive tripsinogen (IRT) at birth,
intermediate tiers consists of CFTR mutation analysis or an IRT
resampling, and as a last step a sweat chloride test is made to
distinguish between NBS false and true positive cases. (3) In Hungary
national NBS program is not available yet. However, the protocol of the
NBS is elaborated for years. (4) This case underlines the need of a
national NBS program of CF in Hungary.
Early diagnosis and CF specific therapy from the early stage may protect
lungs from serious damages and disease progression. It is well known
that countries where NBS was introduced, the median age at the diagnosis
decreased; for example in England from 2,4 years to 3 weeks of age. Mak
et al. compared different provinces in Canada at the same time where NBS
was already introduced and where it was not applied yet. (5) With the
introduction of NBS, CF was diagnosed earlier, pancreatic insufficiency
was less common, mean z-scores for weight-for-age and height-for-age was
higher. The frequency of hospital admission was reduced and there was a
lower prevalence of colonization with Pseudomonas aeruginosa and
Staphylococcus aureus. Lung infections were treated earlier so they did
not cause irreversible lung damage.
Message
Our experience suggests that the lack of national NBS program of CF
leads to delayed diagnosis in Hungary. Introducing NBS of CF may
decrease the age at the time of diagnosis that could lead to a better
quality of life and clinical state of the patients. In the meantime,
clinicians in Hungary should always consider CF as part of their
differential diagnosis at cases with recurrent respiratory infections
and failure to thrive.