Pneumocystis pneumonia B59; J17.3

In 1909, Chagas and Carinii detected the pathogen causing pneumocystis pneumonia in rodents. This was given the name Pneumocystis carinii (Pneumocystis jovecii) in 1914. The actual disease in humans was first described during World War II in malnourished children in Europe. The pathogen was long regarded as a protozoon; in fact, it is a unicellular tubular fungus.

Pneumocystis pneumonia (PCP) is a pneumonia caused by unicellular tubular fungi (Ascomycota).

The organisms of the Pneumocystis group are morphologically very similar, but genetically different. They have host specificity and are transmitted from host to host. Pneumocystis jovecii describes a fungus that occurs exclusively in rodents. Initially, it was mistakenly thought to be the causative agent of Pneumocystis pneumonia in humans. In the meantime it has been proven that the pathogen differs from Pneumocystis carinii in humans and was named "Pneumocystis jirovecii". PCP is interstitial atypical pneumonia, with 50% the most frequent initial manifestation and with 85% the most frequent opportunistic infection in AIDS patients.

pneumocystis jirovecii

Serological screening tests have confirmed that Pneumocystis is spread worldwide. Already in childhood the degree of infestation is > 60 %. The transmission is aerogenic and in case of illness causes mainly pneumonia. However, extrapulmonary forms of the disease can also occur. The presence of pneumocystis does not usually lead to disease in healthy persons.

Only immunosuppression (HIV, immunosuppressive therapy after transplantation or autoimmune diseases, premature births, anorexia, high-dose corticosteroid administration, etc.) can lead to infection by Pneumocystis jirovecii (see also Pneumonia triad).

In the 1980s - without chemoprophylaxis or antiretroviral therapy - 80-90% of HIV-infected persons contracted Pneumocystis pneumonia once or several times.

At that time, the disease was the most frequent cause of death among HIV-infected persons. Pneumocystis leads under immunosuppression to a reaction of the mononuclear cells (PBMC). The alveoli fill with protein-containing material and are damaged. This in turn leads to damage of the pulmonary capillaries and to changes in the surfactant.

In HIV-infected patients, the incidence of PCP correlates inversely with the CD4+ T-cell count:

• In about 80 % of PCP-infected patients CD4 cell counts of < 200 cells/μl are found.
• In response to the infection we find at the same time significantly increased CD8 cell counts.

However, the prognosis of pneumonia depends less on the pathogen density than on the extent and type of the immune response. The CD4+ T-cell counts are not suitable for risk assessment in immunocompromised persons without HIV infection, as this cell type is less specific for this.

In HIV-infected persons, the clinical symptoms begin unspecifically and can sometimes last for weeks. It is not uncommon (50%) for the first diagnosis of HIV infection to be made in the course of PCP. With NON- HIV- patients the course is acute or subacute:

- unproductive cough

- progressive stress dyspnea, which ultimately leads to dyspnea at rest

- Reduction in performance

- Weight Loss

- (later also) fever

HIV-infected persons:

The clinical findings are - apart from candidosis of the oral mucosa - inconspicuous. The absence of candidiasis speaks against PCP in otherwise untreated patients. In the sputum and in the BALF there is abundant pneumocystis.

NON- HIV-infected patients:

Clinical findings: normal. The density of pneumocysts is low and they can only be detected by BALF or biopsy.

- Auscultation: at the beginning inconspicuous; untreated, diffuse rales occur in the further course.

- Lung function: initially a normal oximaemia at rest, under stress a pronounced hypoxaemia; restrictive ventilation disturbance, reduced diffusion capacity (DLCO).

- Rö-Thorax: initially often normal; later on bilateral perihilar infiltrates; in 20-40% of cases the x-ray image remains unremarkable

- CT: in the early stage already diffuse milky glass-like opacities; cysts and/or pneumothorax are often detectable; a normal CT practically excludes pneumocystis pneumonia.

Often LDH elevation due to pulmonary damage; however, normal values do not rule out PCP; LDH correlates positively with the prognosis; leukocytes may be moderately elevated

Laboratory, x-ray, CT and lung function are indicative. However, pathogen detection is required for diagnosis, but Pneumocystis jirovecii does not grow on the usual culture media.

Detection can be done by histopathological staining methods. Grocott staining selectively reveals the cystic wall, while Giemsa staining covers the nuclei of all stages of development. The immunofluorescence technique, on the other hand, has a higher specificity and sensitivity than can be achieved by histopathological examinations.

In addition, a quantitative PCR analysis should always be performed, as this technique has the highest sensitivity. However, the test cannot differentiate between colonisation and infection.

A negative result rules out PCP. A result with > 1450 copies/ml is diagnostic, at values < 1450 copies/ml further diagnostics is necessary, e.g. biopsies by TBB, less often by VATS (Video-Assisted Thoracoscopy)

Since the pathogen density in sputum of non-HIV infected persons is sometimes low, fiberoptic bronchoscopy with BAL is considered the gold standard. Transbronchial or open lung biopsy should only be performed if BAL is negative.

Trimethoprim-Sulfamethoxazole: The product of choice is trimethoprim-Sulfamethoxazole(Cotrimoxazole). Oral administration is possible for mild to moderate courses (PaO2> 70 mmHg or Pa O2 - Pa O2< 35 mmHg under ambient air). Patients with PaO2 < 60 mmHg in ambient air should receive intravenous therapy (TMP 5 mg/kg plus SMX 25 mg/kg every 6-8 hours p.o. - corresponds to 2-3 x 2 tablets of Cotrimoxazol forte per day - or as i.v. administration. Side effects: fever, hyperkalemia, cytopenia, exanthema, hepatitis

TMP plus dapsone: 5mg/kg every 6-8 hours p.o. plus dapsone 100 mg/d p.o. Side effects: haemolysis (in case of G6PD deficiency), methaemoglobinaemia, fever, gastrointestinal disorders, exanthema.

Atovaquone: 2x750 mg/d p.o. Side effects: fever, exanthema. Hepatitis

Clindamycin plus primaquine: 300-450 mg every 6 hours p.o. or 600 mg every 6-8 h i.v. plus primaquine 15-30 mg/d p.o. Primaquine is not approved in Germany and is only available through the International Pharmacy. Side effects: Haemolysis (with G6PD), methaemoglobinaemia, exanthema, neutropenia

Pentamidine: 3-4 mg/kg/d i.v. Side effects: hypotension, azoteemia, arrhythmia, pancreatitis, hypocalcaemia, neutropenia, hepatitis, blood sugar regulation disorders (life-threatening hypoglycaemia may occur days or weeks after the initial infusion!)

Echinocandins such as caspofungin could in principle also be used to treat Pneumocystis jirovecii infections, but this is very unusual to date.

Remark: Antimycotics from the classes of polyenes and triazoles are ineffective against Pneumocystis, because they inhibit the synthesis of ergosterol, which does not occur in this species.

concomitant medication:

Prednisone 2 x 40 mg/d for 5 days, then 1 x 40 mg/d for 5 days, then 1 x 20 mg/d for 11 days p.o. or i.v. (see also below)

In patients with HIV infection, the therapy only responds after > 4-5 days. The therapy duration should be 21 days. Here, a temporary deterioration in respiratory function often occurs shortly after the start of therapy. With simultaneous administration of glucocorticoids, this complication can be prevented - at least in HIV-infected patients with moderate to severe PCP. In mild PCP and non-HIV-infected patients, the benefit of cortisone has not yet been clarified.

In patients without HIV infection we find a faster response to therapy (< 4-5 days). Here a therapy duration of 14 days is sufficient.

Without treatment PCP is always fatal!

Patients who require artificial respiration in the early phase have a high mortality rate (60%). In addition, age, the extent of immunosuppression, pre-existing lung diseases, low serum albumin concentration and the development of a pneumothorax all play a role in mortality.

The prognosis for HIV-infected patients is good with early diagnosis and early therapy. The mortality rate is 15-20% one month after the onset of the disease. In contrast, the prognosis for non-HIV-infected persons is rather poor. Mortality is 40 % despite early therapy.

Prophylaxis

Prophylaxis is indicated in HIV patients who have not yet received antiretroviral treatment or who have a history of throrstomatitis or candidosis of the esophagus. This can only be discontinued if the helper cells are > 200 /μl for at least 3 months.

In non-HIV infected patients there are no laboratory parameters with which the susceptibility to PCP can be estimated. It has been shown that especially patients with prolonged high-dose cortisone administration are sensitive to Pneumocystis Pneumonia. The administration of glucocorticoids, from which on chemoprophylaxis should be started, is currently still discussed in different ways. In any case, patients receiving >20 mg prednisone equivalent daily for more than 30 days should be treated prophylactically.

Patients after expired pneumocystis pneumonia should always receive prophylaxis.

The drug of choice is trimethoprim-sulfamethoxazole (TMP-SMX) 1 x 1 tablet per day (400/80 mg or 800/160 mg) p.o.. Allergic reactions are more frequent. Unless these are life-threatening complications, a gradual increase in dose should be attempted.

Alternatives are: Dapsone 2 x 50 mg/d or 1 x 100 mg/d p.o. Dapsone 1 x 50 mg/d p.o., plus pyrimethamine 1 x 50 mg p.o., plus folinic acid 1 x 25 mg p.o. (Folinic acid prevents the bone marrow toxicity of pyrimethamine)

Dapsone 1x 200 mg weekly p.o., plus pyrimethamine 1 x 75 mg weekly p.o., plus folinic acid 1 x 25 mg weekly p.o. Pentamidine 1 x 300 mg monthly via Respirgard-II nebuliser; NW: cough, bronchospasm

Atovaquone 1 x 1500 mg/d p.o.

TMP-SMX 3 x 960 mg weekly (160 mg TMP and 800 mg SMX corresponds to 1 tablet TMPSMX Forte)

Pneumocystis carinii is not an actual synonym, even if it is sometimes found as such (see also definition).

1. Ewig S et al (2018) Pneumonia under immunosuppression 39-46
2. Gerok et al.(2007) Internal Medicine - Reference work for the medical specialist 419-421
3. Herold at al. (2018) Internal Medicine 387-388
4. Kasper DL et al (2015) Harrison's Principles of Internal Medicine 1358-1362
5. Kasper DL (2015) Harrisons Internal Medicine 1662-1673
6. Loscalzo J (2010) Harrison's lung medicine and intensive care 189-194
7. Doyle L et al (2017) Pneumocystis PCR: It Is Time to Make PCR the Test of Choice. Open Forum Infect Dis .