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\title{Cryptococcal meningoencephalitis and pneumonia in a HIV positive
patient: A case report}



\author[1]{Hamed  Mehdinezhad}%
\author[1]{Sara  Ghadir}%
\author[1]{parviz amri maleh}%
\author[1]{Alian  Akhondzadeh}%
\author[1]{Mana  Baziborun}%
\affil[1]{Babol University of Medical Science}%


\vspace{-1em}



  
  \date{May 24, 2024}


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Case report

\textbf{Cryptococcal meningoencephalitis and pneumonia in a HIV positive
patient: A case report}

\textbf{Running title:} Cryptococcal meningoencephalitis and pneumonia

\textbf{Hamed Mehdinezhad\textsuperscript{1}, Sara
Ghadir\textsuperscript{2}, Parviz Amri Maleh\textsuperscript{1,} Alian
Akhondzadeh\textsuperscript{3}, \emph{Mana
Baziboroun\textsuperscript{3}*}}

\textsuperscript{1}Clinical Research Development Unit of Rouhani
Hospital, Babol University of Medical Sciences, Babol, I.R. Iran

\textsuperscript{2} student research committee, Babol University of
Medical Sciences, Babol, I.R. Iran

\textsuperscript{3}Infectious Diseases and Tropical Medicine Research
Center, Health Research Institute, clinical research of development unit
of Rouhani Hospital, Babol University of Medical Sciences, Babol, I.R.
Iran Iran

\textbf{Keywords} : meningoencephalitis, Cryptococcus, HIV, meningitis,
encephalitis

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

Corresponding author: Mana Baziboroun , fellowship of infection in
immunocompromised and transplant patients, infectious disease department
of Ruhani hospital, Babol University of Medical Science, Babol, Iran,
postal Code: 47176-41367

\emph{E-Mail: manabaziboron@gmail.com}

Tel:011-32238284

Mob: +989111153051

\textbf{Abstract}

Cryptococcus is a serious opportunistic infection among human
immunodeficiency virus (HIV) positive people. Meningoencephalitis is the
most common manifestation of cryptococcal infection, while pulmonary
cryptococcosis is often neglected due to nonspecific clinical and
radiological presentation leading to a delay in diagnosis and
disseminated disease. Here, we reported a 67-year-old man with newly
diagnosed HIV who presented with concurrent cryptococcal
meningoencephalitis and pulmonary cryptococcosis that admitted with the
complaint of dyspnea and productive cough for 1.5 months, worsening
shortness of breath, fever and weight loss since 15 days prior to
admission. He also had severe oral candidiasis. Lung computed tomography
(CT) revealed ill-defined subpleural cavitary lesion in left lower zone
with bilateral diffuse ground glass opacity and air bronchogram. His HIV
PCR test was positive with absolute CD4 count less than 50 cells/mm3.
After starting antiretroviral therapy (ART), he gradually developed a
headache and decreased level of consciousness. Cerebrospinal fluid (CSF)
analysis revealed 450 cells, predominantly lymphocytes, with protein of
343mg/dl and glucose of 98 mg/dl (corresponding blood glucose 284
mg/dl). CSF India ink staining was positive for crypococcus spp.
Liposomal amphotericin B in combination with fluconazole (due to the
unavailability of flucytosin) was stated. He was intubated because of
hypoxia and his bronchoalveolar lavage was positive for Cryptococcus
spp. too. He died 2 weeks after starting antifungal therapy based on
this study it should be mentioned that neurologic and respiratory
symptoms may be the first presentation of acquired immunodeficiency
syndrome.

\textbf{Abbreviations:}

Human Immunodeficiency Virus (HIV)

Computed Tomography (CT)

Antiretroviral Therapy (ART)

Cerebrospinal Fluid (CSF)

\textbf{Intorduction}

As we know, Cryptococcosis is considered as the most common fungal
infection of the brain. It's also considered as the most common fungal
infection in people positive for HIV (1). Cryptococcosis as an important
opportunistic infection with a high mortality and morbidity rate can be
caused by two encapsulated cryptococcus species: Cryptococcus neoformans
and Cryptococcus gattii. Available data shows that C.gattii is
responsible for the initiation of disease in immunocompetents but
C.neoformans is responsible for invasive disorders in immunocompromised
patients (2). Polysaccharide capsule was described as its virulence
factor that is composed of glucuronoxylomannan (its major component),
galactoxylomannan, and mannoproteins which can activate phagocytosis by
alveolar macrophages following inhalation. Since they can make it
through phagocytosis, these fungal cells spread hematogenously via cell
lysis or vomocytosis (a nonlytic process in which an immune response is
being prevented) (1, 3). After exposure, these fungal cells can cause
asymptomatic condition or they can cause pneumonia-like manifestations.
They can also lead to some neurological clinical conditions such as
meningitis, meningoencephalitis, and cryptococcomas (4). Regardless of
the decreasing rate of cryptococcosis, world still has a high
cryptococcal infection incidence in immunocompromised patients (5). The
most common route to cryptococcosis diagnosis is through testing
biological body fluids for cryptococcal antigen (6).

Here, we report a case with newly diagnosed HIV and concurrent
cryptococcal pneumonia and meningoencephalitis.

\textbf{Case history/examination}

A 67-year-old male patient was admitted to our hospital with complaints
of continuous and gradually worsening shortness of breath, fever,
productive cough, headache, loss of apetite, and weight loss since 1.5
months ago which got worse 15 days prior to admission. Meanwhile, he had
visited the outpatient clinic several times and had no improvement. He
was a chef from a city from north of Iran with 5 children. Medical
history revealed inguinal surgery for hernia,10 years ago and prostate
surgery, 1 year ago. His social history, familial history and drug
history were unremarkable, except seretide and salbutamol that were
started in 15 recent days. The physical examination revealed a somnolent
patient with 13/15 score on the Glasgow coma scale, who was febrile
(T:38.8 \selectlanguage{ngerman}°C) and had BP:90/60, RR:32 breaths/ min, PR:98 breaths/ min. He
was in respiratory distress and required oxygen therapy to maintain
saturation, so that his O2 saturation was 76\% while he was breathing
ambient air and with mask 92\%. Severe thrush was detected in the
oropharynx. In addition, bilateral crackles were detected on pulmonary
auscultation.

\textbf{Methods}

A CT scan of the chest revealed an ill-defined subpleural cavitary
lesion in left lower zone with bilateral diffuse ground glass opacity
and internal air bronchogram. There were cavitary nodules in right lung.
Some small mediastinal lymph nodes were also present (Fig. 1) According
to the symptoms and pattern of lung CTscan, he was prescribed with
meropenem, levofloxacin, vancomycin, and co-trimoxazole, as well as
hydrocortisone and nystatin drop. He was admitted to the ICU due to his
low oxygen saturation. The results of laboratory tests showed as
following: WBC: 10200/L, Neutrophil: 95\%, normocytic anemia, Platelet:
233000 U, ESR (Erythrocyte Sedimentation Rate): 63 mm/hr, CRP (C-
Reactive Protein): 95, LDH: 831, Urine culture: negative, Urine
analysis: normal, Blood culture: negative. On sputum smear: No AFB
(acid-fast bacillus) was seen

and, sputum culture was negative. Blood levels of electrolytes were
normal, as were the results of liver-function and kidney-function tests,
Rheumatologic markers and

PCR from nasopharyngeal specimen for COVID-9 and Influenza virus.

\textbf{Conclusion and Results}

Due to high suspicion of HIV infection, the diagnosis was verified by
serological testing with absolute CD4 count less than 50 cells/mm3.
After starting antiretroviral therapy(ART) including dolutegravir,
tenofovir and emtricitabin, his level of consciousness gradually
decreased and his headache got worse. A computed tomography (CT) scan of
the brain showed no abnormality. The patient underwent a lumbar puncture
and cerebrospinal fluid (CSF) analysis revealed:10 cells, predominantly
lymphocytes, Protein: 343 mg/dl, and Glucose: 98 mg/dl (corresponding
blood glucose 284 mg/dl). The direct microscopic examination of CSF with
India ink staining showed budding and non-budding yeast compatible with
crypococcus spp. As shown in Figure 2. Liposomal amphotericin B in
combination with fluconazole (due to the unavailability of flucytosin)
was started with serial lumbar puncture for management of elevated
intracranial pressure. After one week, He was intubated due to worsening
hypoxia. Then a bronchoscopy was performed and his bronchoalveolar
lavage was also positive for Cryptococcus spp. Respiratory distress
worsened rapidly and he died 2 weeks after starting antifungal therapy.

In conclusion, as early diagnosis of cryptococcal infection is the key
to improving outcomes, any newly diagnosed HIV patient presenting with
subacute or chronic headache, particularly those who are CD4-deplete,
should be investigated for cryptococcal meningitis.

\textbf{Discussion}

Cryptococcosis by C.neoformans, can be considered as a life-threatening
condition in HIV-positive patients. There has an increase in the
incidence of cryptococcal meningitis but its prevalence is reducing (7).
The most common route of entry for cryptococcus in immunocompromised
patients is through inhalation of spores or desiccated yeast cells (8).
In patients with immunosuppression, cryptococcus can start causing
symptoms and acute respiratory distress syndrome can rapidly appear as a
consequence. After infecting the lungs, these fungi can spread
hematogenously and reach the CNS (9). Available data propose that
currently there are two mechanisms by which cryptoccocus can enter the
CNS. One is to migrate directly through endothelium by transcytosis and
other one is being carried inside macrophages. Their polysaccharide
capsule has anti-phagocytic propreties (10). There can be several signs
and symptoms for CNS involvement, however the rate of patients who
develop them is low. These manifestations involve headache, nausea,
fever, memory loss, altered level of consciousness, confusion, seizures,
and hearing impairment (1). Cryptoccocal pneumonia manifests as fever,
productive cough, and chest pain and it can radiologically mimic lung
cancer or metastasis, lung tuberculosis, and bacterial pneumonia. It can
also be asymptomatic and diagnosed coincidentally (11). The radiological
findings in immunocompromised patients may include cavitation, lobar
opacities, nodules, pleural effusion, and lymphadenopathy (12).

Patients who are positive for HIV infection specially with low CD4 cell
count and with subacute or chronic headache should be considered as
candidates for lumbar puncture to investigate cryptococcal
meningoencephalitis. In addition to CSF cell count, CSF culture, and
india ink, we can assess CrAg in CSF. We can also detect CrAg in serum.
We can also use blood culture, chest X ray, head CT scan, and MRI (13).
Lateral flow assay (LFA) with a sensitivity of more than 95\% and a
specificity of 100\% is a new laboratory tool being used for detecting
cryptococcal antigen (1).

The initial therapy should contain antifungal drugs. A two-week therapy
with amphotericin B at 3 mg/kg/day and flucytosine at 100 mg/kg/day as
induction phase. Afterwards, therapy should be continued with
fluconazole for eight to 12 months as consolidation phase (12). Studies
suggested that a combination of amphotericin B with flucytosine can have
a better fungicidal effect with lower risk of failure in treatment
rather than a combination of amphotericin B with fluconazole (14).

A better clinical outcome for patients with meningoencephalitis is
related to the choice of initial therapy and handling raised
intracranial pressure. An elevated opening pressure of more than 25 cm
of CSF requires serial lumbar punctures to reduce the pressure to less
than 20 cm of CSF (15).

As we can see in presented case ART should be delayed at least 2 weeks
after the start of antifungal therapy, due to the occurrence of immune
reconstitution inflammatory syndrome (IRIS) resulting in worsening
symptoms and sometimes death as happened in our patient.

\textbf{Key clinical messages}

Early diagnosis of cryptococcal infection is the key to improving
outcomes, any newly diagnosed HIV patient presenting with subacute or
chronic headache, particularly those who are CD4-deplete, should be
investigated for cryptococcal meningitis.

\textbf{Ethical approval and consent to participate}

The ethics committee of Babol University of Medical Sciences, Iran
(Approval no. IR.MUBABOL.HRI.REC.1401.079)

\textbf{Human and animal rights}

No animals were used in this research. The human research procedure was
in accordance with the standards set forth in the Declaration of
Helsinki principles of 1975, as revised in 2013
(http://ethics.iit.edu/ecodes/node/3931).

\textbf{Availability of data and materials}

The authors confirm that the data supporting the results and findings of
this study are available within the article.

\textbf{Conflict of interest and funding}

The authors declare no conflict of interest, financial or otherwise.

\textbf{Acknowledgments}

The authors of the present survey would like to thank the patient who
provided us with complete information about his illness and Clinical
Research Development Unit of Rouhani Hospital of Babol University of
Medical Sciences.

\textbf{Consent statement:} Written informed consent was obtained from
the patient to publish this report in accordance with the journal's
patient consent policy

\textbf{Authorship contributions} :

M.B, H.M, S.Gh, P.A and A.AKh. Conceived of the presented idea, designed
the study, M.B. wrote the paper, Conceived of the presented idea,
designed the study, developed the theory and performed the computations,
supervised the findings of this work. All authors discussed the results
and contributed to the final manuscript.

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3. Johnston SA, May RC. C ryptococcus interactions with macrophages:
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4. Kakizaki MIT, Melhem MDS. CRYPTOCOCCOSIS: A bibliographic narrative
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5. Zhao Y, Ye L, Zhao F, Zhang L, Lu Z, Chu T, et al. Cryptococcus
neoformans, a global threat to human health. Infectious Diseases of
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6. Skipper C, Abassi M, Boulware DR. Diagnosis and management of central
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Case Report. International Journal of Caring Sciences.
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8. Shuai S-Y, Xiong L, He X-L, Yu F, Xia Q, Zhou Q. A unique case report
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9. Akrim Y, Ouasif H, Zrikem H, El Hakkouni A, Ouassif H. Disseminated
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12. Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill
RJ, et al. Clinical practice guidelines for the management of
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America. Clinical infectious diseases. 2010;50(3):291-322.

13. Kabanda T, Siedner MJ, Klausner JD, Muzoora C, Boulware DR.
Point-of-care diagnosis and prognostication of cryptococcal meningitis
with the cryptococcal antigen lateral flow assay on cerebrospinal fluid.
Clinical infectious diseases. 2014;58(1):113-6.

14. Rajasingham R, Rolfes MA, Birkenkamp KE, Meya DB, Boulware DR.
Cryptococcal meningitis treatment strategies in resource-limited
settings: a cost-effectiveness analysis. 2012.

15. Srichatrapimuk S, Sungkanuparph S. Integrated therapy for HIV and
cryptococcosis. AIDS research and therapy. 2016;13:1-15.\selectlanguage{english}
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\textbf{Figure (1).} Patient`s lung CT scan that shows an ill-defined
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\textbf{Figure (2).} India ink staining of CSF that shows budding and
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