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Cryptococcosis

Busse Buschke (Manifestation)

Cryptococcosis is an invasive fungal infection principally caused by Cryptococcus neoformans and Cryptococcus gattii in some cases. Cryptococcosis occurs worldwide, and are acquired through inhalation of contaminated aerosols. The majority of patients who develop cryptococcosis are immunocompromised, and the principal infections are those of the lung and meningitis. Treatment involves systemic antifungal therapy.


Presentation

Infection can affect virtually any part of the body in Cryptococcosis, including the skin, eyes, genitourinary and gastrointestinal tract [6], but the two most common sites are the lungs and the central nervous system. The signs and symptoms depend on the affected organ [7].

Pulmonary cryptococcosis can manifests in various stages, ranging from asymptomatic disease to possibly life-threatening pneumonia. Usually, a pneumonia-like disease, including symptoms such as a cough, dyspnea, chest pain, and fever, can be observed. Other symptoms, such as fatigue, are also reported.

Cryptococcosis of the central nervous system (primarily causing meningitis, and possibly meningoencephalitis), occurs after hematogenous dissemination of fungi from the respiratory tract, and includes symptoms such as a headache, fever, neck stiffness, nausea, vomiting, and altered mental state and consciousness [8]. Severe cases may present with memory loss, seizures, and coma.

It is important to note that cryptococcosis may affect more than one organ, and patients may present with symptoms that indicate both pulmonary and central nervous system infection.

Presentations which may indicate an involvement of other organs include rash, arthritis, endocarditis, hepatitis, peritonitis, lymphadenopathy, and other organ-related manifestations.

Malaise
  • Other symptoms include fever, weight loss, malaise and coughing up blood or hemoptysis. On rare occasions, pleural effusion occurs. Severe pulmonary diseases and respiratory syndromes are more likely to occur in those with weakened immune systems.[news-medical.net]
  • A large number of pulmonary infections due to cryptococcosis may go unreported; its symptoms include fever, malaise, and a dry cough.[britannica.com]
  • Clinical Presentation: Most patients present with symptoms or signs of subacute meningitis or meningoencephalitis, with fever, malaise, nausea, vomiting, lethargy, and altered mental status.[ajnr.org]
  • This is associated with cough, pleurisy, malaise and fever. Free organisms are seen in mucopurulent exudate with little or no inflammatory infiltrate.[histopathology-india.net]
  • Immunosuppressed patients may present with mild-to-moderate symptoms, including fever, malaise, dry cough, chest pain. Severe infection may lead to pneumonia or adult respiratory distress syndrome.[dermnetnz.org]
Weight Loss
  • loss People with a healthy immune system may have no symptoms at all.[nlm.nih.gov]
  • Other symptoms include fever, weight loss, malaise and coughing up blood or hemoptysis. On rare occasions, pleural effusion occurs. Severe pulmonary diseases and respiratory syndromes are more likely to occur in those with weakened immune systems.[news-medical.net]
  • Remember that HIV-infected patients may be asymptomatic or present with nonspecific symptoms, eg lethargy, weight loss.[patient.info]
  • The most frequent presenting symptoms were cough (75%), dyspnea (62.5%), weight loss (25%), and hemoptysis (25%). Radiographically, in most cases (75%), atelectasis/infiltrates were observed.[journals.lww.com]
Fatigue
  • A 73-year-old man presented with fatigue and anorexia and underwent FDG PET/CT scan to evaluate a right lung nodule revealed by a chest CT.[ncbi.nlm.nih.gov]
  • Lung symptoms may include: Difficulty in breathing Cough Chest pain Other symptoms may include: Bone pain or tenderness of the breastbone Fatigue Skin rash, including pinpoint red spots ( petechiae ), ulcers, or other skin lesions Sweating -- unusual,[nlm.nih.gov]
  • Types localized cryptococcosis wound cryptococcosis or cutaneous cryptococcosis pulmonary cryptococcosis menigeal cryptococcosis (cryptococcal meningitis) cryptococcal meningoencephalitis systemic cryptococcosis Clinical synopsis Symptoms include fever, fatigue[humpath.com]
Veterinarian
  • Disclaimer: This website is not intended to replace professional consultation, diagnosis, or treatment by a licensed veterinarian. If you require any veterinary related advice, contact your veterinarian promptly.[web.archive.org]
Cough
  • The first patient was a 17-year-old female, had fever, cough, headache and intractable vomiting as well as itchy water bumps on her skin and upper limbs. The cutaneous eruption prompted the accurate diagnosis.[ncbi.nlm.nih.gov]
  • In the minority of cases where symptoms do develop, signs may vary from a non-specific cough to more severe symptoms such as shortness of breath (dyspnea) or pleuritic chest pain.[news-medical.net]
  • People may have no symptoms or may have headache and confusion, a cough and an achy chest, or a rash, depending on where the infection is. The diagnosis is based on culture and examination of tissue and fluid samples.[merckmanuals.com]
  • Lung symptoms may include: Difficulty in breathing Cough Chest pain Other symptoms may include: Bone pain or tenderness of the breastbone Fatigue Skin rash, including pinpoint red spots ( petechiae ), ulcers, or other skin lesions Sweating -- unusual,[nlm.nih.gov]
Sputum
  • Abstract Cryptococcus neoformans was cultured from the sputum, bronchial washings, or pleural fluid of 17 patients, 9 of whom were thought to have cryptococcal pulmonary disease.[annals.org]
  • The physical exam may reveal: Abnormal breath sounds Fast heart rate Fever Mental status changes Stiff neck Tests that may be done include: Blood culture to differentiate between the two fungi CT scan of the head Sputum culture and stain Lung biopsy Bronchoscopy[nlm.nih.gov]
  • Sputum cytology for malignant cells and acid-fast stain for acid-fast bacilli was negative. HIV antibody test was negative and CD4 count - 502 cells/microliter.[ccij-online.org]
  • This is achieved using a sample of cerbrospinal fluid, sputum or urine. The sample is placed on a glass slide and stained with special dyes which help to detect the fungi when the sample is analysed under the microscope.[news-medical.net]
  • A tissue or body fluid sample (blood, cerebrospinal fluid or sputum) can be tested for antigen and also cultured for the fungus. Additionally, a chest x-ray or CT scan of the lungs, brain or other parts of the body can be helpful in the diagnosis.[health.hawaii.gov]
Pleural Effusion
  • Routine chest X-ray film showed pleural effusion, and his retropositive status was detected for the first time.[hoajonline.com]
  • A new infiltrate in the right lung and pleural effusion associated with fever developed on August 15, 2004. Cultures of the pleural effusion drawn on August 19 yielded Cryptococcus neoformans (isolate A).[nejm.org]
  • Masses ( n 2), lymphadenopathy ( n 2), areas of consolidation ( n 2), areas of hazy increased attenuation ( n 1), pleural effusion ( n 1), and areas of cavitation ( n 1) were uncommon.[pubs.rsna.org]
  • On rare occasions, pleural effusion occurs. Severe pulmonary diseases and respiratory syndromes are more likely to occur in those with weakened immune systems. In healthy patients, infection may be self-limited.[news-medical.net]
  • effusion may also be present.[radiopaedia.org]
Hemoptysis
  • Five weeks after admission, pulmonary consultation was requested to evaluate fever, worsening dyspnea, wheezing, and moderate hemoptysis.[journals.lww.com]
  • Other symptoms include fever, weight loss, malaise and coughing up blood or hemoptysis. On rare occasions, pleural effusion occurs. Severe pulmonary diseases and respiratory syndromes are more likely to occur in those with weakened immune systems.[news-medical.net]
  • No patient had hemoptysis.[academic.oup.com]
  • A patient with pulmonary cryptococcosis may present with mild-to-moderate symptoms, including fever, malaise, cough with scant sputum, pleuritic pain, and hemoptysis (rare). Unusual findings include rales or pleural rub.[emedicine.medscape.com]
  • Some patients may also have hemoptysis and hypoxemia. In HIV-infected patients, pulmonary cryptococcosis is more severe and has a more acute onset than that in other hosts.[aidsrestherapy.biomedcentral.com]
Hoarseness
  • All patients presented with persistent or progressive hoarseness. Lesions were predominantly on the true vocal cords (79%), 38% associated with an adherent white exudate or leukoplakia.[ncbi.nlm.nih.gov]
Subcutaneous Nodule
  • In the disseminated form, one can observe the development of cutaneous infections in the form of papulae, pustules, or subcutaneous nodules.[intechopen.com]
Headache
  • Fever, headache, and vomiting were the most common symptoms. The most common sites were the central nervous system (CNS), followed by the lungs.[ncbi.nlm.nih.gov]

Workup

The combination of clinical findings, as well as patient history, can provide sufficient evidence to investigate Cryptococcosis as a possible illness. Patient history may reveal an underlying disease or risk factors, such as HIV infection, or immunosuppressive therapy, which may predispose the patient to cryptococcal infection.

Workup involves radiographic and laboratory procedures. In a case of respiratory complaints, plain chest X-ray should be performed, and it can reveal single or multiple nodules in the parenchyma, which can mimic malignant tumors because of its shape and appearance. Other findings, such as hilar lymphadenopathy, pleural effusion, and lobar or diffuse infiltrates are also observed.

If there are symptoms indicating a CNS infection, computed tomography (CT) or magnetic resonance imaging (MRI) of the endocranium should be performed, and they can reveal hydrocephalus or such findings as the presence of one or more cryptococcomas. The severity of the disease has been established to be in correlation with the severity of findings in neuroimaging studies, particularly for HIV-positive patients [9].

Because numerous pathogens may cause similar symptoms and signs of pulmonary and central nervous system involvement, several diagnostic procedures are performed to exclude other pathogens as causative agents, but also to confirm Cryptococcosis. Lumbar puncture may show very high opening pressure, as well as abnormal protein and glucose content. In addition to biochemical investigations, a CSF sample is obtained for microbiological investigation, principally for antigen detection and culture. Antigen detection in CSF is both very sensitive and specific, and detects the presence of Cryptococcus neoformans rapidly. A definite confirmation can be given by cultivation of the obtained CSF or blood, and microscopy examination, with both standard as well as India ink stainings, which can clearly visualize budding yeasts and provide results within several days. Biopsy and tissue samples are also possible diagnostic tools, but antigen detection, culture, and microscopic examination are sufficient to obtain a diagnosis in virtually all cases.

Laboratory tests should also include the evaluation of the immune system, including leukocyte count, which may show leukopenia, with either neutropenia, lymphopenia, or both. Additionally, if patients are HIV positive, CD4+ T cell counts should be performed.

Pulmonary Infiltrate
  • We made a provisional diagnosis of pulmonary infiltrates with eosinophilia syndrome with eosinophilic meningitis.[lungindia.com]
  • A 46-year-old woman with extensive pulmonary infiltrates. N Engl J Med 2002; 347:517-524 [Google Scholar] 15. Lam CL, Lam WK, Wong Y, et al. Pulmonary cryptococcosis: a case report and review of the Asian-Pacific experience.[ajronline.org]
  • Fluconazole (400 mg [6 mg per kg] per day) should be used for six to 12 months in patients with mild to moderate symptoms without diffuse pulmonary infiltrates.[aafp.org]
  • For mild-to-moderate symptoms and focal pulmonary infiltrates, treatment with fluconazole (400 mg daily for 12 months) combined with effective ART is appropriate (BIII) .[aidsinfo.nih.gov]
  • Pulmonary cryptococcosis with severe symptoms and/or diffuse pulmonary infiltrates should be treated with regimens identical to those for disseminated disease and meningitis [ 2, 9 ].[aidsrestherapy.biomedcentral.com]
Multiple Pulmonary Nodules
  • pulmonary nodules or masses, which mimics primary or metastatic malignancy. [5], [9], [10] A large solitary cryptococcoma replacing the majority of a lobe, as seen in our case, is highly unusual.[ccij-online.org]
  • The most common radiographic manifestations of pulmonary cryptococcosis consist of single or multiple pulmonary nodules, segmental or lobar consolidation, or a reticulonodular pattern of opacities [ 3, 5 - 7 ].[ajronline.org]
Cryptococcus Antigen
  • Semiquantitative CRAG latex titers ( Cryptococcus Antigen Latex Agglutination Test System; Immy, Inc.) were measured by 2-fold serial dilution on cryopreserved ( 80 C) samples in Minnesota.[doi.org]
Colonic Ulcer
  • This case illustrates that a colonic ulcer, although rare, could be cryptococcosis.[ncbi.nlm.nih.gov]
Brain Edema
  • Cerebral herniation due to generalized brain edema complicated CM in 2 patients. In both patients, cerebral herniation developed despite performance of ventriculostomy or placement of a ventriculoperitoneal shunt.[doi.org]
  • In addition to antifungal therapy, appropriate symptomatic therapy is necessary, such as antiedematous therapy in the setting of increased cerebrospinal fluid pressure and brain edema.[symptoma.com]
Pleural Effusion
  • Routine chest X-ray film showed pleural effusion, and his retropositive status was detected for the first time.[hoajonline.com]
  • A new infiltrate in the right lung and pleural effusion associated with fever developed on August 15, 2004. Cultures of the pleural effusion drawn on August 19 yielded Cryptococcus neoformans (isolate A).[nejm.org]
  • Masses ( n 2), lymphadenopathy ( n 2), areas of consolidation ( n 2), areas of hazy increased attenuation ( n 1), pleural effusion ( n 1), and areas of cavitation ( n 1) were uncommon.[pubs.rsna.org]
  • On rare occasions, pleural effusion occurs. Severe pulmonary diseases and respiratory syndromes are more likely to occur in those with weakened immune systems. In healthy patients, infection may be self-limited.[news-medical.net]
  • effusion may also be present.[radiopaedia.org]

Treatment

Treatment of Cryptococcosis depends on the severity of disease and the site of infection. Patients who have asymptomatic colonization may not require therapy, and those with mild pulmonary involvement, without evidence of extrapulmonary infection, may receive oral fluconazole 200-400mg PO q24h for a prolonged period of time.

However, patients with serious disease require intravenous administration of antifungals, such as those with symptomatic pulmonary, central nervous system or disseminated infections, and primary choice is amphotericin B in doses of 0.5 to 1.0 mg/kg IV q24h, usually combined with flucytosine 25mg/kg q6h for al least 14 days or longer [10]. The primary parameter of a duration of treatment is the presence of sterile cultures of CSF or blood. Additional treatment options include liposomal amphotericin B 4 mg/kg IV q24h, combined with fluconazole 400mg either PO or IV q24h, or a combination of fluconazole and flucytosine for 4-6 weeks [11]. In addition to antifungal therapy, appropriate symptomatic therapy is necessary, such as antiedematous therapy in the setting of increased cerebrospinal fluid pressure and brain edema.

Once the infection is resolved with therapy, consolidation therapy is necessary to prevent recurrent infections, and it consists of oral administration of fluconazole 400-800mg once daily, for about 10 weeks [12]. Once this course of therapy is finished, the third and last course of therapy includes suppression therapy, which is important to patients who were severely immunocompromised at the time of infection, and consists of administration of fluconazole per os 200mg once daily, for 6-12 months. Patients who improve CD4+ T cell counts (> 200/mm3) may stop this regimen.

Patients with HIV infection, particularly those who are severely immunocompromised, should not be started on immediate antiretroviral therapy, as it has been established that deferral of therapy for several weeks drastically improved survival outcomes [13].

Prognosis

An early diagnosis is essential for a good prognosis because Cryptococcosis can be successfully treatable with systemic antifungal therapy.

However, an important factor is the general condition of the patient. Despite available therapy, Cryptococcosis can still be a fatal disease.

Etiology

This fungal infection is principally caused by Cryptococcus neoformans, and in a small number of cases, Cryptococcus gattii. Since initial discovery in 1895 [2], the fungal genus Cryptococcus have been extensively researched. These fungi are oval, yeastlike organisms, with the diameter ranging from 2-20 µm. Cryptococcus species are encapsulated, and their polysaccharide capsule is the principal virulence factor. They are classified into different serotypes according to the composition of the polysaccharide capsule.

This fungus replicates through asexual reproduction, specifically by budding, and the replication process is rather slow, which accounts for a slowly developing infectious process, and initial asymptomatic course of the disease.

Epidemiology

Fungal genus Cryptococcus has a worldwide distribution, which is particularly true for Cryptococcus neoformans. It is a ubiquitous microorganism that is found in soil which contains bird droppings [3]. It is established that the replication cycle starts in birds, primarily pigeons, who do not develop an infection (presumably because of high body temperatures ) but shed the fungus in feces, which ends up in soil. Inhalation of contaminated aerosols is the principal route of acquisition of the disease. A somewhat different cycle is proposed for Cryptococcus gattii, which was initially restricted to tropical and subtropical regions, and associated with Eucalyptus trees. Outbreaks in the northwestern Pacific have questioned these theories.

Cryptococcosis can be divided by the affected population. Namely, Cryptococcus neoformans causes infection primarily in immunocompromised individuals, which may include patients suffering from various diseases, or receiving specific forms of therapy:

On the other hand, Cryptococcus gattii infection is primarily reported in immunocompetent individuals.

Sex distribution
Age distribution

Pathophysiology

Cryptococcosis starts with inhalation of aerosols contaminated with the fungus, and the initial site of replication is the respiratory tract [5]. Under physiological circumstances, when the fungi reach the lower respiratory tract, alveolar macrophages are recruited, and together with migrating leukocytes are involved in an inflammatory response, which results in the fungus elimination. However, in cases of immunosuppression, the fungus is able to proliferate and spreads to other sites through blood, and can establish either focal or disseminated infection. Cryptococcosis also may remain dormant in the lungs.

The primary virulence factor of Cryptococcus is the polysaccharide capsule, which prevents binding of complement, prevents phagocytosis, interferes with a secretion of proinflammatory cytokines, and allows the fungi to replicate inside the human host.

Prevention

Prevention of cryptococcosis can rarely be achieved through avoiding exposure because the organism can be found all over the world in soil, and in locations habituated by pigeons, so the principal preventive measure is managing of possible underlying diseases that can predispose individuals to this infection, and regular follow-ups of patients who are at risk.

Summary

Cryptococcosis is caused by Cryptococcus neoformans, a ubiquitous fungal pathogen, while Cryptococcus gattii is responsible for a small percentage of cases [1]. Inhalation of contaminated aerosol which contains avian fecal material is the mode of acquisition of Cryptococcus neoformans infection, while Cryptococcus gattii infection has been associated with contaminated eucalyptus trees, and has been primarily linked to habitation in the tropical and subtropical regions. However, recent outbreaks in the northwestern Pacific suggest other modes are involved in its transmission. Human-to-human transmission has not been documented yet for either species. Once the fungus reaches the respiratory tract, several factors play a role in establishing an infection, including the virulence of the strain, a size of inoculum, and most importantly, host defenses. The majority of patients who develop infection by Cryptococcus neoformans are immunocompromised, most commonly due to human immunodeficiency virus (HIV) infection, with CD4+ T-cell counts of < 200/mm3, while patients with malignant diseases, transplant recipients, or those receiving chemotherapy, are also particularly susceptible to this infection. On the other hand, Cryptococcus gattii infection is more frequently observed in immunocompetent individuals. Cryptococcus species primarily infects the respiratory system, which results in pneumonia-like disease. Patients may be asymptomatic, present with mild respiratory complaints, or have severe bilateral infiltrates with significant consequences on lung function. In addition to pneumonia-like disease, infection of the central nervous system as a result of hematogenous spread from the lungs, poses a greater threat to the patient, and can manifest as meningitis or meningoencephalitis. The diagnosis is made by culture of cerebrospinal fluid (CSF) or blood, or other material, depending on the site of infection. A particular staining, India ink, as well as standard Gram staining is used for identification of cultured fungi, but rapid and reliable confirmation can be obtained through direct identification of cryptococcal antigen in blood or CSF through serological testing. Treatment comprises administration of systemic antifungals, such as amphotericin B, flucytosine, and fluconazole. Prevention of cryptococcosis primarily involves improving the immune status.

Patient Information

in serious casesCryptococcosis is an infection caused by two fungi, Cryptococcus neoformans and Cryptococcus gattii. Cryptococcus neoformans is present in bird feces. Human infection occurs by inhalation of particles from soil that contain this fungus. Humans can inhale the contaminated soil, but they may not develop an infection, and a substantial number of individuals have an asymptomatic infection by this fungus, as their immune system is able to fight off the fungus. However, when patients are immunocompromised, such as patients with HIV or those receiving immunosuppressive therapy and chemotherapy, they are at risk of developing this infection. On the other hand, Cryptococcus gattii, which is not transmitted through bird feces, but instead has been associated with an acquisition from eucalyptus trees, causes infection in immunocompetent and otherwise healthy individuals, although this organism is much rarely observed as a cause of Cryptococcosis.

The most common type of infection in Cryptococcosis is pulmonary, with manifestations such as cough, chest pain, fever, increased breathing rate, and sputum production. Infection of the central nervous system manifests with fever, headache, vomiting, and in severe cases, altered consciousness, seizures, and even coma. Cryptococcosis may also target the eyes, skin, kidneys, liver, prostate, breasts, and other organs, and sometimes more than one organ can be affected.

Cryptococcosis may be life-threatening, and it is one of the most common life-threatening fungal infections in patients with HIV infection and AIDS, which is why prompt diagnosis and treatment is necessary for achieving a good result. The diagnosis is made by identification of fungi through different tests, most common being detection of the fungi from cerebrospinal fluid. In addition to microbiological confirmation, imaging studies, such as chest X-rays, CT and MRI of the head, as well as other accompanying blood tests, should be performed to assess the focus, as well as the severity of the infection.

Treatment includes intravenous and oral administration of antifungals, such as amphotericin B, flucytosine or fluconazole. Once the infection has resolved, antifungal therapy may be continued for up to a year through oral intake of fluconazole, to prevent recurrent infection. In addition to antifungal therapy, symptomatic and supportive therapy are necessary to support the patient during administration of antifungal therapy. If this infection is treated promptly, and properly, a good outcome can be expected. Despite well-defined guidelines, it is still a life-threatening infection in serious cases.

Prevention in high-risk patients can be achieved through proper management of the underlying disease, since avoiding exposure to areas contaminated with this fungus, is highly unlikely.

References

Article

  1. Lin X, Heitman J. The biology of the Cryptococcus neoformans species complex. Annu Rev Microbiol. 2006;60:69-105.
  2. Buschke A. Ueber eine durch Coccidien Hervergerufene Krankheit des menschen. Deutsche Med. Wochenschr. 1895;21(3):14.
  3. Perfect JR, Casadevall A. Cryptococcosis. Infect Dis Clin North Am. 2002;16:837-874.
  4. Dromer F, Mathoulin-Pelissier S, Fontanet A, et al. Epidemiology of HIV-associate cryptococcosis in France (1985-2001): comparison of the pre-and post-HAART eras. AIDS. 2004;18:555-562.
  5. Chang WC, Tzao C, Hsu HH, et al. Pulmonary cryptococcosis: comparison of clinical and radiographic characteristics in immunocompetent and immunocompromised patients. Chest. 2006;129(2):333-340.
  6. Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2006;20:507-544.
  7. Sabiiti W, May RC. Mechanisms of infection by the human fungal pathogen Cryptococcus neoformans. Future microbiol. 2012;7(11):1297-1313.
  8. Jarvis JN, Harrison TS. Pulmonary cryptococcosis. Semin Respir Crit Care Med. 2008;29:141-150.
  9. Charlier C, Dromer F, Leveque C, et al. Cryptococcal neuroradiological lesions correlate with severity during cryptococcal meningoencephalitis in HIV-positive patients in the HAART era. PLoS One. 2008;3:e1950.
  10. Jarvis JN, Dromer F, Harrison TS, et al. Managing cryptococcosis in the immunocompromised host. Curr Opin Infect Dis. 2008;21:596-603.
  11. Perfect JR, et al. Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(3):291-322.
  12. Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011;183:96-128.
  13. Boulware DR, Meya DB, Muzoora C, et al.Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis. N Engl J Med. 2014;370:2487-2498.

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Last updated: 2019-07-11 22:06