Pneumocystis pneumonia (PCP) is a lung disease caused by a common organism previously called Pneumocystis carinii, but which has now been renamed P. jiroveci. This was originally thought to be a protozoan, but more recently research has found that it is an atypical fungus. It is relatively common throughout the population and does not cause problems in people with healthy immune systems. However, if the immune system is damaged the organisms can grow in the lungs, causing PCP. In people with HIV, the organisms can also sometimes grow in other parts of the body such as the lymph nodes, bone marrow, spleen, liver and, occasionally, the eye. Illness caused by P. jiroveci is sometimes collectively described as pneumocystosis.

PCP was first noticed in children who were immunosuppressed because of malnourishment. People with HIV are potentially at risk from PCP if their CD4 cell count falls below 200 cells/mm³, although most cases occur among people with CD4 cell counts below 100 cells/mm³. PCP was a common cause of death among people with AIDS during the early years of the epidemic, and it is still one of the most common AIDS illnesses. However, treatment and prophylaxis for PCP have improved dramatically, and now it is much more unusual for PCP to be fatal.

Studies have also shown that HIV-positive smokers develop PCP two to three times faster than HIV-positive people who do not smoke. One study found, encouragingly, that ex-smokers who had given up at least a year before they entered the study seemed to develop PCP no quicker or more frequently than non-smokers. The researchers suggested that smoking may directly affect the immune cells in the lungs, activating HIV infected cells and reducing the ability of immune cells in the lung tissues and airways to combat infections.

Other factors which may increase a person's risk of PCP include gardening, breathing chemical irritants, previous pneumonia, camping and hiking (Navin 2000).

In the United Kingdom, there were 178 new cases of PCP in HIV-positive people in 2003, accounting for 28% of all AIDS diagnoses

Symptoms of PCP

The most common early symptoms of PCP are shortness of breath or fever, which people with HIV should always take seriously. Other warning signs can include a persistent dry cough that does not produce any phlegm, and occasionally pain or tightness in the chest.

At first the symptoms may only be noticeable after exercise, but as the condition worsens, shortness of breath can become a noticeable problem during minor activity such as climbing the stairs, or eventually while doing nothing but relaxing.

Weight loss, malaise and diarrhoea are also frequently associated with developing PCP.

New or recurrent pneumonia has been observed in a number of studies of patients starting antiretroviral therapy. It is standard practice to administer corticosteroids to patients with moderate-to-severe PCP, to decrease the inflammatory response to dying organisms.

Diagnosis

Doctors use a number of different tests to diagnose PCP, such as chest X-rays and measurements of the amount of oxygen in the blood. PCP should be suspected when an HIV-positive person has a cough with shortness of breath and high fever, and anti-PCP treatments may be started presumptively. However, a variety of other infections can cause identical symptoms, and the only way to diagnose PCP definitively is to look for the Pneumocystis organisms themselves.

Tests can detect Pneumocystis organisms in sputum (spit and mucus) obtained by a process called sputum induction or from fluid recovered from the lung using an instrument called a bronchoscope. Sputum induction is necessary because ordinary sputum does not come from deep enough in the chest to be able to detect PCP. Breathing in a mist of salty water makes people cough deeply enough that PCP and other organisms in the lungs are coughed up. This procedure can be uncomfortable, and may be less reliable than bronchoscopy.

A new technique for diagnosing PCP is under development. Using this approach, the person with suspected PCP gargles a salt solution and then spits it into a cup. Previously, crude PCR testing could indicate the presence or absence of the Pneumocystis organisms but couldn't identify who had PCP. The new technique involves quantifying the Pneumocystis in the gargled solution, thus allowing doctors to identify people with PCP disease (Larsen 2002). Commercialisation of such a test would allow for an easy and low cost method for diagnosing PCP.

In bronchoscopy, a fibre-optic instrument is passed through the mouth or nostrils into the lungs. Salty water is squirted in and sucked out again. A fine pair of forceps is occasionally used to remove a tiny piece of tissue. This tissue and the salty water are then looked at, under a microscope, for PCP. Again, this procedure can be uncomfortable, and usually the nostrils and throat are treated with a local anaesthetic and a sedative injection is given. This is usually a type of morphine, which can also help to reduce coughing, diazepam (Valium) or a similar drug. Bronchoscopy can sometimes cause collapse of the lung called pneumothorax.

In many centres, sputum induction is the first test which is performed. If this does not confirm PCP or any other infection, a bronchoscopy is done.

Prevention

It is clearly established that a person's risk of developing PCP rises significantly when their CD4 count falls below 200 or 250 cells/mm³. A significant proportion of people do not notice any warning symptoms before the onset of the pneumonia. People with HIV are therefore normally advised to start taking PCP prophylaxis (preventive therapy) when their CD4 cell count falls below 200 to 250 cells/mm³, or if they develop other AIDS-defining illnesses, to try to prevent a first attack of PCP (primary prophylaxis). The presence of an explained persistent daily fever above 38°C (100°F) or Candida in the throat is also a sign of increased risk of PCP, regardless of CD4 cell count.

People who have been treated for an episode of PCP are advised to continue to take low doses of anti-PCP medications to try to prevent a further episode (secondary prophylaxis or maintenance therapy). A person who has sustained rebound in CD4 cell count above 200 to 250 cells/mm³ due to successful antiretroviral treatment, may consider ceasing prophylaxis. See Stopping prophylaxis below for more details.

In resource-limited settings the World Health Organization recommends that all individuals with CD4 cell counts below 500 cells/mm³ should receive co-trimoxazole as prophylaxis against PCP and bacterial infections.

With any prophylaxis it is important to balance the risk of side-effects and the inconvenience of taking the treatment against the risk of developing the opportunistic infection in question. However, the wisdom of using PCP prophylaxis is one of the few aspects of HIV / AIDS medicine where there is near consensus. Some researchers have calculated that PCP prophylaxis may in itself prolong survival.

Options for prophylaxis

The four main options for PCP prophylaxis are:

• Co-trimoxazole (Septrin / Bactrim).

• Aerosolised pentamidine (Pentacarinat).

• Atovaquone (Wellvone).

• Dapsone.

Co-trimoxazole is the drug most commonly prescribed to prevent PCP. Standard dosing is one double-strength (960mg) co-trimoxazole tablet daily.

A large American study published in 1995 found that co-trimoxazole, aerosolised pentamidine and dapsone are all equally effective for people with CD4 cell counts above 100 cells/mm³. However, for people with CD4 cell counts below 100 cells/mm³, co-trimoxazole and dapsone were substantially more effective at preventing PCP than aerosolised pentamidine (Bozzette 1995).

Several studies have shown few or no attacks of PCP among people taking one double-strength co-trimoxazole tablet a day over long periods of follow-up. It is used as prophylaxis at much lower doses than those used for treating active PCP, and side-effects are therefore much less common. People who have a mild allergic reaction may be able to develop a tolerance for the drug by reducing the dose and then gradually building it up to standard doses again over a period of weeks. Using this kind of dose-escalation when starting prophylaxis for the first time has also been shown to reduce the proportion of people who discontinue treatment due to allergic effects.

Some clinics prescribe thrice-weekly rather than daily co-trimoxazole. In late 1997, a trial found that there is no difference between the effectiveness of these regimens at preventing PCP, but people receiving daily co-trimoxazole had lower rates of bacterial pneumonia. Among people receiving secondary prophylaxis, those receiving daily co-trimoxazole lived longer than those receiving the thrice-weekly regimen.

Because co-trimoxazole is absorbed into the body through the gut and distributed around the body in the bloodstream, it can also help to prevent pneumocystosis outside the lungs. It also offers a real level of protection against toxoplasmosis and many bacterial infections.

Resistance to co-trimoxazole may develop, especially among people previously exposed to the drug, and it is associated with a greater risk of death (Helweg-Larsen 1999; Kazanjian 2000).

Aerosolised pentamidine consists of the drug pentamidine isethionate which is converted into a fine mist and breathed directly into the lungs from a machine called a nebuliser. The usual dosing schedule is 300mg once a month, which is all that is needed to ensure that any Pneumocystis organisms which are present in the lungs are kept under control. Some clinics recommend once fortnightly doses to be extra safe. The drug can be administered in hospital or from a portable nebuliser at home. These cost about £120, or can sometimes be obtained from social services. It may be important to lie down flat during the inhalation and to move from side to side so the drug gets to all parts of the lungs.

Aerosolised pentamidine is less effective than co-trimoxazole. Trials suggest that over a one-year period about 10 to 20% of people using it develop a first episode of PCP. The study ACTG 021 found that co-trimoxazole is also more effective than nebulised pentamidine as secondary prophylaxis (i.e. for people who had recovered from an initial episode of PCP).

People receiving pentamidine at 300mg monthly were over three times more likely to experience recurrence of PCP within one year than those taking one double-strength tablet of co-trimoxazole every day. Some research suggests that higher doses of aerosolised pentamidine (300mg every two weeks or 600mg every month) are safe and may be more effective than 300mg every month.

The advantage of aerosolised pentamidine is that it causes few side-effects. Many people complain of a metallic taste during the treatment, but this soon disappears. The drug can also cause coughing fits, especially among smokers.

However, its chief disadvantage is that it only reaches the lungs, so it offers no protection against pneumocystosis in other parts of the body. Even in the lungs the inhaled mist may not reach all the lung tissue evenly. Some people with HIV also find the regular visits to the clinic very inconvenient. Intramuscular injections of pentamidine may be an alternative to aerosolised treatment.

Dapsone is another tablet-form antibiotic. Studies suggest that it is about as effective as co-trimoxazole. It causes side effects such as rashes, nausea and occasionally hepatitis in about 10 to 15% of recipients. People who are allergic to co-trimoxazole are sometimes also allergic to dapsone. A French study comparing aerosolised pentamidine versus dapsone in combination with iron supplements found an increased risk of death among dapsone recipients. However, this result is unexplained.

Amongst people who cannot tolerate co-trimoxazole, research has found that atovaquone is as effective as dapsone at preventing PCP while causing fewer side-effects (El-Sadr 1998). Dapsone is, however, a much cheaper drug. In a similar study population, atovaquone was demonstrated to be equivalent to aerosolised pentamidine, though at a cost of a greater incidence of side-effects (Chan 1999).

Other prophylactic options include sulphadiazine plus pyrimethamine (Daraprim) and dapsone plus pyrimethamine. These are already widely used as anti-malarial drugs. They are likely to offer prophylaxis against toxoplasmosis as well as against PCP, but not against bacterial infections. There is a risk of skin rashes and both drugs may make the blood side effects of AZT (zidovudine, Retrovir) worse.

The antibiotic azithromycin (Zithromax) is also active against PCP. A study in which everyone was already taking specific PCP prophylaxis found that people who received azithromycin as prophylaxis for Mycobacterium avium intracellulare (MAI) had their risk of developing PCP reduced by a half compared with people who received rifabutin (Mycobutin; Dunne 1999).

Stopping prophylaxis

People who have experienced a sustained increase in their CD4 count due to highly active antiretroviral therapy (HAART) may stop PCP prophylaxis with little risk of developing PCP. A number of large studies have now shown that most people who have sustained immune recovery may safely stop PCP prophylaxis while their CD4 cell count remains above 200 to 250 cells/mm³. For example, the EuroSIDA study reported only one case of PCP among over 500 people on HAART who stopped PCP prophylaxis with an average CD4 cell count of 310 cells/mm³ (Weverling 1999).

The safety of ceasing prophylaxis also applies people who have had a previous bout of PCP or a very low CD4 cell count, as well as people with detectable viral load. These groups were thought to be at the greatest risk of PCP if they ceased prophylaxis. However, several studies show these individuals may safely stop PCP prophylaxis. For example, no cases of PCP were reported among 325 Europeans with a history of PCP who stopped prophylaxis with an average CD4 cell count of 350 cells/mm³ (Ledergerber 2001; also see Lopez 2000; Furrer 2001; Koletar 2001; Zellweger 2004).

An editorial in the New England Journal of Medicine has confirmed that stopping secondary PCP prophylaxis is safe for people with sustained immune recovery. Previously the journal had warned against ceasing prophylaxis in high risk groups (Weverling 1999; Dworkin 2001).

Based on these results, United States Public Health Service guidelines now allow for discontinuation of both primary and secondary PCP prophylaxis. That is, people can cease PCP prophylaxis if they have had a CD4 cell count above 200 to 250 cells/mm³ for at least three months, even if they have previously had a bout of PCP. In the United Kingdom, doctors report that many people who have sustained their CD4 cell counts above 250 cells/mm³ are stopping PCP prophylaxis. The Medical Research Council are collecting data on the effects of ceasing PCP prophylaxis.

If a persons CD4 cell count once again falls below 200 to 250 cells/mm³, prophylaxis should be recommenced.

Very rarely, individuals with strong immune recovery may develop PCP (Valentine 2000; Koval 2002).

Prophylaxis in children

PCP is the most common manifestation of AIDS in children and is responsible for the majority of deaths in infants with HIV infection in the United Kingdom. Less than half of the children who develop PCP are alive three months later despite intensive treatment. Given this poor prognosis, prophylaxis is very important.

However, the need for PCP prophylaxis is far more problematic in infants than in adults. The most frequent and severe cases of PCP occur in babies under six months old, and this is the period of time when it is most difficult to be sure whether or not the child of an HIV-positive mother is itself infected with HIV. When deciding when is the best time to begin PCP prophylaxis for an infant born to an HIV-positive mother there are therefore three different options to be considered.

The first option is for all children born to HIV-positive women to take PCP prophylaxis from around three weeks old and continue until it is clear whether or not the child is infected with HIV. As described below, current United States guidelines endorse this approach, recommending that all infants born to HIV-infected mothers received co-trimoxazole beginning at four to six weeks. The problem with this approach is that for the one child who is prevented from getting PCP, about 50 will have received prophylaxis unnecessarily, either because they are not infected with HIV, or they are infected but are not fast progressors and are thus not at risk from PCP. There is, however, the advantage that co-trimoxazole may help to prevent other bacterial infections.

Another option is to start PCP prophylaxis as soon as a definitive diagnosis of HIV infection is made. There are also problems with this approach. For example, the infant may develop PCP before the diagnosis is made, and infants who are not fast progressors may receive PCP prophylaxis unnecessarily. For children who are not fast progressors, co-trimoxazole helps prevent bacterial infections and early PCP prophylaxis may be beneficial in the long term.

The third option is to start PCP prophylaxis if the CD4 cell count falls below certain levels. These are different from adult values and depend on age. In the United States, the Centers for Disease Control and Prevention (CDC) are constantly reviewing and changing the guidelines and many paediatricians are sceptical about whether it is possible to establish standards for beginning PCP prophylaxis based on CD4 cell count. A strategy based on CD4 cell counts means that the baby must be followed very carefully and have their CD4 cell count measured at least once a month, as they can fall very quickly.

In 1995 the CDC released revised guidelines for PCP prophylaxis in children. They recommended beginning PCP prophylaxis at four to six weeks of age for all children born to HIV-positive women and continuing prophylaxis for one year, or until the child is proven not to be infected with HIV. For children aged over between one and five years, the CDC recommends PCP prophylaxis for those with CD4 cell counts below 500 cells/mm³, or a CD4 percentage below 15%. For children aged between six and twelve years, PCP prophylaxis is recommended at a CD4 cell count below 200 cells/mm³ or 15%. In addition, children who have had an episode of PCP should receive lifelong prophylaxis to prevent recurrence, regardless of their CD4 cell count or clinical status.

Due to a lack of data, current American guidelines do not make any clear statements about the cessation of PCP prophylaxis in children with immune recovery.

See Anti-HIV therapy: Options for children for information on use of co-trimoxazole prophylaxis in children in resource-limited settings.

Treatment

Co-trimoxazole is the standard first-line treatment for an attack of PCP, although alternative regimens are available. The choice of which drug to use will depend on experience at the clinic, the doctors' preference, the severity of the infection and the patient's history of allergic reaction to drugs' side effects or drug resistance.

Co-trimoxazole is made up of two agents: trimethoprim and sulphamethoxazole. The standard recommended dosages are trimethoprim 15 to 20mg/kg per day and sulphamethoxazole 75mg/kg per day by continuous drip or injection (three to four injections daily) for a few days and then in tablet form for a total of three weeks. Co-trimoxazole is as effective as alternative PCP treatments and has the advantage that it also works against bacteria and some other infections. Its major disadvantage is that more than 50% of people experience side-effects from intravenous co-trimoxazole. These can be mild, such as rash or nausea, that can easily be controlled with other agents such as metoclopramide (Maxolon) or by dose reduction. In a minority of cases, side-effects can be major, including a shortage of white blood cells (leukopenia) or platelets (thrombocytopenia) or kidney problems, requiring a switch to another treatment.

Alternative treatments for PCP are:

• Trimethoprim (Monotrim / Trimopran) and dapsone.

• Pentamidine.

• Trimetrexate.

• Atovaquone.

• Clindamycin (Dalacin C) and primaquine.

In the combination of dapsone plus trimethoprim, dapsone is used in place of the sulphonamide drug which is responsible for most of the side-effects with co-trimoxazole. It is usually used only for mild to moderate PCP. Dapsone (100mg per day) is given by mouth and the trimethoprim (5mg/kg per day every six to eight hours is given intravenously or by mouth depending on the severity of the infection. The combination is also effective against toxoplasmosis but less effective against any bacteria that may be present.

Rarely, dapsone can cause vomiting or rashes. It may also damage blood cells, so should always be given with the vitamin folinic acid. This is especially common in people with inherited blood disorders, usually in black patients, or in people on drugs that cause anaemia, such as high-dose AZT (zidovudine, Retrovir), ganciclovir (Cymevene) and cytotoxic chemotherapy.

Intravenous pentamidine is used in people who experience serious side effects with co-trimoxazole or with dapsone and trimethoprim. It is given as a daily drip 3 to 4mg/kg per day. It appears to be less effective than co-trimoxazole and has no effects against other infections. Its side-effects include shortage of neutrophils (neutropenia), kidney problems and changes in blood pressure and blood sugar levels, sometimes causing temporary diabetes. Another side effect may be pancreatitis so it may be particularly unsafe for people on ddI (didanosine, Videx / VidexEC).

Trimetrexate is a licensed treatment for people who do not respond to, or are allergic to co-trimoxazole. It has to be taken with folinic acid to protect human cells against the drug's toxicities and target its effects against the PCP organisms.

Atovaquone is a broad-spectrum antiprotozoal compound. It seems to be about as effective as co-trimoxazole in treating mild to moderate PCP, and has fewer side-effects. Atovaquone is no longer available in tablet form. Instead, it is produced as a fruit-flavoured liquid suspension. The preferred dose is 750mg (5ml) twice daily for at least 21 days. Atovaquone is now approved as a treatment for PCP for people who cannot take co-trimoxazole.

The combination of clindamycin (600mg intravenously four times a day followed by capsules) plus primaquine tablets (15mg per day) has been shown to be effective in those who fail to respond to co-trimoxazole. This combination has not been specifically approved for use against PCP. It is considered an experimental second line drug which causes a high rate of side-effects. Doctors may suggest trying it if co-trimoxazole has not worked after around six days. About 50% of people develop a rash when they take this drug. One study found clindamycin plus primaquine to be as effective in treating PCP as standard treatment, and clindamycin did not cause more side effects (Toma 1998).

In moderate-to-severe PCP, corticosteroids such as prednisolone may be given alongside the PCP treatment. Although these drugs are immunosuppressive, they have been shown to improve the success of treatment by dampening down inflammation in the lung. However, there may be an increased risk of other infections, such as thrush, herpes or bacterial infections, during the time the steroids are being taken. Some studies have suggested that steroids increase the risk of developing cytomegalovirus (CMV) disease, and that people with PCP who also have CMV in their lungs have an increased death-rate if they are treated with corticosteroids. There seems to be no benefit in using added corticosteroids in cases of mild-to-moderate PCP.

An experimental drug called WR 6026 is being developed as a treatment for PCP (Petty 1999).

Other features of treatment

Patients with PCP usually require bed rest, if not at the time of diagnosis, usually after treatment. In addition, oxygen is usually given through a face mask, as it speeds recovery. A special mask to raise the pressure of oxygen can sometimes be used.

Aspirin or paracetamol can be useful for reducin fever, improving malaise and increasing the oxygen level in the body.

PCP or the drugs used to treat it can lead to loss of appetite. Food supplements or replacements can be supplied by a dietician if needed. Anti-nausea medication may also help.

It is fairly common for people with PCP also to have other infections in their lungs, such as Streptococcus or Staphylococcus. This increases the risk that the PCP will be serious. Other antibiotics are often be given alongside the PCP treatment in order to suppress or eliminate these other infections.