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Managing pneumocystis pneumonia

Dr Michel Brauner/ISM/SCIENCE PHOTO LIBRARYA 34-year-old Hispanic, 60kg man with a recent diagnosis of HIV and dysphasia presented to the on-call service at his local HIV clinic, complaining of hoarseness (dysphonia), fevers, night sweats, lethargy, dizziness, weight loss and loss of appetite, thirst, occasional cough, enlarging skin plaques, cognitive changes and vomiting. He was put on the acute surgical admissions ward while awaiting a side room on the specialist infectious diseases ward.
The patient’s medical history is described in Panel 1.

Panel 1: Medical history

History of presenting complaint

  • Dizzy spells for 4/12, increasing in frequency — now daily
  • Weight loss; 22kg in one year
  • Night sweats for 3–4/52, feverish but no rigors

Previous medical history

  • HIV diagnosed via A+E admission (December 2011); CD4 30cells/mm3, VL 570,000 copies/ml
  • Dysphasia
  • Referred to tuberculosis clinic (for night sweats and cough). He did not attend (DNA) for bronchoscopy or follow-up appointments.

Medication history on admission

  • No known drug allergy (NKDA)
  • Smoker, 10/day for 10+ years, recently cut down
  • Not on highly active antiretroviral therapy (HAART)
  • Not on any prophylaxis for opportunistic infections (OIs)
  • No herbal medicines or recreational drugs
  • Paracetamol 1g bd prn (over the counter)

Investigations and diagnosis

The following investigations were performed before the patient was transferred to the infectious diseases ward:

  • CD4 (20cells/mm3); viral load 300,000 copies/ml (13/03/2012)
  • Magnetic resonance imaging (head) — “no abnormalities detected” (NAD)
  • Computed tomography scan (head) — NAD
  • Fundoscopy and other ophthalmological review — no obvious haemorrhage, no retinitis
  • Lumbar puncture (LP) — NAD
  • Cerebrospinal fluid (CSF) — Gram stain negative and culture negative after 5/7; polymerase chain reaction (PCR) negative for herpes simplex viruses 1 and 2, varicellar zoster virus, cytomegalovirus, Epstein Barr virus and John Cunningham virus (JCV)
  • Serum cryptococcal antigen (CrAg) — negative
  • High resolution CT scan (chest) — changes suggest Pneumocystis carinii pneumonia (PCP; see Panel 2)
  • Chest X-ray — abnormal; cavitating lung lesions
  • Bronchoscopy and brocho-alveolar lavage — PCP confirmed
  • Acid fast bacilli (AFB) stain and culture — negative
  • Bloods — haemoglobin 10.6g/dL (13.0–17.0); mean corpuscular volume 100fL (80–99); platelets 90x109/L (150–400); white cell count 2.43x109/L (3.0–10.0); neutrophils 1.92x109/L (2.0–7.5); arterial blood gas on air PaO2 recorded in notes as 15.72kPa (10–13.0 [NB, result likely to be erroneous — it is impossible to be this high on room air — this was later repeated and came back as 10.3.); liver function normal; renal function normal; C-reactive protein (CRP) 30.3mg/L (0–2.0)
  • Blood cultures — no significant growth
  • Significant observations — febrile, tachycardic and tachypnoeic; temperature 38.4C (36.5–37.5); BP 116/58mmHg (120/80–140/90); pulse 100bpm (50–100); respiratory rate 18 breaths/min (12–14); saturations at rest 95 per cent (97–100) on room air

Panel 2: Basics of pneumocystis pneumonia

Pneumocystis pneumonia is an opportunistic infection caused by Pneumocystis jirovecii, formerly known as Pneumocystis carinii (hence the abbreviation PCP). This fungus is common in the general population, but most infections (often called pneumocystosis) occur in the immunocompromised, and almost 90 per cent of cases occur in HIV-seropositive patients with CD4 T-cell counts <200cells/mm3 or a CD4 percentage<14.1 Other predictive factors for PCP in HIV patients not receiving effective highly active antiretroviral therapy (HAART) include non-adherence to prophylaxis (see below), oral candidiasis, oral hairy leukoplakia, unintentional weight loss, recurrent bacterial pneumonia, previous PCP and a high plasma HIV load.1

Most cases are associated with respiratory symptoms but the lymph nodes, bone marrow, spleen, liver and eyes can be affected. Common early symptoms of PCP are shortness of breath (often first noticed on exertion but experienced at rest as the condition worsens) or fever, or both. Other warning signs include a dry cough and chest pain or tightness. Weight loss, diarrhoea and generally feeling unwell are also possible.

Diagnostic investigations include chest X-ray, computed tomography, blood gases (PaO2), sputum culture, bronchoscopy with alveolar lavage and lung biopsy. The disease can be classed as mild, moderate or severe, based on symptoms, PaO2, SaO2 and chest radiograph.1 It can cause fatal respiratory failure so patients need early and effective treatment.

Treatment First-line treatment regimens are as follows:1

  • For moderate-severe disease (PaO2 <9.3kPa), intravenous co-trimoxazole 120mg/kg/day IV 3/7 then 90mg/kg/day IV 18/7 (21 days total)
  • For mild–moderate disease (PaO2 >9.3kPa), oral co-trimoxazole 90mg/kg/day, 21/7

Alternative regimens include:1,2

  • Clindamycin 600–900mg IV qds or tds or 300–450mg orally tds or qds plus primaquine 15–30mg od, 21/7
  • In severe disease pentamidine 4mg/kg IV od 21/7 may be considered
  • In mild disease dapsone 100mg PO od and trimethoprim 20mg/kg/day PO 21/7 or atovaquone 750mg bd PO 21/7 may be considered

Giving steroids early, as an adjunct to treatment, has been shown to reduce mortality in moderate to severe cases.1 Oral or intravenous corticosteroids should be started in all cases of suspected moderate–severe PCP with a PaO2<9.3kPa or SaO2<92 per cent1 breathing room air on admission or extensive infiltrates on the chest X-ray.2 For example, prednisolone 40mg bd days 1–5, 40mg od days 6–10 and 20mg od days 11–21 or methylprednisolone IV at 75 per cent of this dose.1

Prophylaxis PCP prophylaxis is recommended for all patients with a CD4 count persistently <200cells/mm3, a CD4 percentage <14 per cent, persistent candida or an AIDS defining illness.1,2 The recommended regimen is co-trimoxazole 480 or 960mg od or 960mg three times a week:1,2  Alternative regimens include:1,2

  • Dapsone 50–100mg od (plus 50–75mg pyrimethamine per week to cover toxoplasmosis)
  • Nebulised pentamidine 300mg every four weeks (NB, avoid if active tuberculosis is a possibility)
  • Azithromycin 1.25g once a week
  • Atovaquone 750mg bd

If the patient tests positive for toxoplasmosis then either the co-trimoxazole or the dapsone plus pyrimethamine regimen should be used.

HAART Early initiation of HAART is favoured in HIV patients with PCP.1 The optimal start time, however, remains undetermined; the potential for immune reconstitution inflammatory syndrome (IRIS; which is more likely if there is active disease) must be borne in mind. The improvements in systemic and local immunity following continuous use of HAART translate into a very low risk of PCP if prophylaxis is discontinued in populations with CD4 counts sustained over 200 cells/mm3 for more than three months.1 Prophylaxis may be stopped, therefore, if the patient on HAART has a CD4 count >200 for three to six months and viral load<50. A discussion with the patient’s HIV consultant is required for stopping outside of this situation.2

The patient was not given any treatment for presumed opportunistic infections until the diagnosis of PCP was confirmed, which was six days into admission. Following the bronchoscopy and AFB stain, tuberculosis was ruled out and the patient was removed from respiratory isolation.
The diagnosis was HIV disease resulting in PCP (mild to moderate), dysphasia and dizziness of unknown cause, candidal stomatitis and seborrhoeic dermatitis.

Management

The following medicines were prescribed:

  • Dalteparin 2,500 units SC od for thromboprophylaxis (low dose due to low platelets)
  • Clotrimazole plus hydrocortisone 1 per cent cream bd for dermatitis
  • Ensure liquid 250ml tds to address weight loss
  • Co-trimoxazole 3.6g po bd for PCP (3 x Septrin Forte and 1 x Septrin to reduce unit dose number; at UCLH we give 120mg/kg day for days 1–2 then reduce to 90mg/kg. Although co-trimoxazole is usually given in three or four divided doses, the patient had tolerated bd dosing — no rash — for several days before arriving at the infectious diseases ward and this dose was kept for ease of administration and compliance.)
  • Prednisolone 40mg po bd (Although this patient’s PCP fell between mild and moderate classes the consultant insisted on steroids because of the cavitating lesions. PaO2 had been incorrectly recorded in the notes.)
  • Fluconazole 100mg po od for oral candida  
  • Paracetamol 1g po prn for fever or pain was continued (infrequent dosing unlikely to mask symptoms of recovery)

On transfer to the infectious diseases ward treatment for PCP had been started, although the first 24 hours of dosing had been omitted (see later). Co-trimoxazole has a high oral bioavailability and the prescribers decided that oral dosing was sufficient in this case. P jirovecii is an unusual fungus that does not have sterol in its cell wall and its mitochondria are similar to bacterial mitochondria but the exact mechanism of co-trimoxazole’s antiprotozoal action is unknown.

Although G6PD status should have been ascertained before prescribing co-trimoxazole, this was missed.

About 50 per cent of people treated with co-trimoxazole experience side effects.3 These commonly include rashes, headache, nausea, diarrhoea, leukopenia and hepatic inflammation. Skin rashes are particularly common among HIV-positive patients and more likely at high doses. These should be taken seriously, with dose reduction or treatment cessation as necessary, due to the risk of severe reactions such as Stevens-Johnson syndrome.4

In addition to markers of infection (CRP, WCC, neutrophils, temperature, etc), full blood count, urea and electrolytes, and liver function should be monitored twice weekly during PCP treatment. On admission both the patient’s platelets and neutrophil counts were low. Co-trimoxazole can cause neutropenia and thrombocytopenia, therefore it was particularly important to monitor this patient’s full blood count to check a further fall in his counts did not occur. Neutrophil count improved throughout the patient’s hospital stay, to 5.39x109/L.

Glucose in blood and urine should be monitored daily while patients are on steroids. The team did not believe it necessary to add gastroprotection with an H2 antagonist or proton pump inhibitor to steroid treatment.

Although the patient had vomited on the day of admission, this did not continue so no antiemetics were given. Despite the candida he did not have any swallowing problems.

The treatment began to work: observations became stable (afebrile, improved blood gases and respiratory rate, decreased CRP) and the patient felt healthier — he had no shortness of breath, further dizziness or blurred vision, just a slight cough. He was discharged with close follow-up. Medication on discharge was:

  • Clotrimazole plus hydrocortisone 1 per cent cream bd 7/7
  • Ensure 250ml tds
  • Fluconazole po 100mg od 3/7
  • Co-trimoxazole po 2.88g bd to complete 21 days treatment, then 480mg od (prophylaxis) thereafter
  • Prednisolone po 40mg bd 3/7, 40mg om 5/7, then 20mg om 11/7


The patient had a follow-up appointment in clinic post discharge, with a plan to start HAART upon completion of PCP treatment. (Note that because the patient had a low CD4 count, some places may initiate HAART sooner.) Prophylaxis with co-trimoxazole was to continue until CD4 was sufficiently and consistently raised on HAART.

Role of the pharmacist

The pharmacist had a pivotal role in patient care throughout this case, ensuring the appropriateness of therapy, providing advice, and supplying medicines. For example, on admission the patient had been vomiting and if this had continued the pharmacist would have had to ensure that appropriate formulations were supplied — IV

co-trimoxazole and fluconazole would have been essential. The team asked for advice on how to reduce the prednisolone, which I based on the British HIV Association (BHIVA) guidelines and the patient’s condition.

Pharmacists also play a key role in medicines management, such as medicines reconciliation, prescription monitoring (including for potential toxicities) and documentation. It is important to ensure that the drug, dose and duration are appropriate for the indication being treated and to query prescribing outside guidelines, such as the steroids in this case.

The pharmacist also needs to communicate with continuing care services at discharge, including HIV and dietitian follow up and smoking cessation as appropriate.

Learning points

I investigated why the first 24 hours of treatment with co-trimoxazole had been omitted.

The nursing staff on the acute surgical ward had documented the reason as being that the drugs were unavailable on the ward. They had contacted the on-call pharmacist for supply, but there was some miscommunication and the nursing staff misinterpreted the advice they were given believing the dose was incorrect. This resulted in the medication chart not being sent to the pharmacy for supply and no medicine being obtained from the specialist ward or the emergency drugs cupboard (EDC). The nurses on the acute surgical ward were not familiar with the dosing and use of co-trimoxazole and were unaware of its importance. They were advised of the need to avoid missed doses and reminded of the National Patient Safety Agency “Reducing harm from omitted and delayed medicines in hospital” alert.

The on-call pharmacist had queried the use of oral co-trimoxazole to treat PCP, and asked the nurses to confirm this information before sending the chart to pharmacy. The nurses were asked to confirm that oral rather than IV was required and told that if they required a supply they could either get some from the specialist ward or send the chart to the pharmacy. The on-call pharmacist assumed nursing staff had obtained a supply
elsewhere and was busy so did not follow up the query. I advised the on-call pharmacist that the use of oral co-trimoxazole is recommended in both BHIVA and our trust guidelines for mild or moderate disease and informed him of the outcome of this case.

Patient counselling

The patient was given several new medicines and was counselled on their indications, how long they should be used for and potential side effects. In particular, he was advised to report any new rash or worsening rash to his HIV team.

The importance of completing treatment was stressed and the patient appeared willing to engage in care. Prophylactic use was also explained.

This decision would balance the risks to the patient, eg, immune reconstitution inflammatory syndrome (IRIS) against the benefits of improved immune system, with a decreased viral load and increased CD4 count.

Smoking cessation advice would have been a possible intervention but on admission the patient had been advised to cut down and that smoking cessation support was available. It is important not to overwhelm the patient with information and smoking cessation can be targeted again at a later date when the patient has recovered from the PCP.

Case comment: Chinyere Okoli, lead pharmacist HIV services, North Middlesex University NHS Trust

Patients who present with opportunistic infections such as PCP are potentially very complex. It is unusual that a patient recently diagnosed with such a low CD4 count was not started on co-trimoxazole prophylaxis. Perhaps this patient was lost to follow-up or was not adherent to treatment, although this was not detailed in the drug history. It would have been interesting if this patient had been taking co-trimoxazole at the time of PCP diagnosis.

The author rightly notes that early initiation of HAART is favoured in patients with PCP, and that evidence is limited, so the optimal initiation time remains to be determined. It is worth noting that “early” initiation would be within two weeks of PCP treatment and not necessarily on the same day.

One of the key contributions pharmacists can make when looking after a patient is to monitor for toxicity of the medicines we supply. In this case the pharmacist would need to be proactive and monitor the patient’s full blood count — blood dyscrasias are possible especially with high doses and prolonged courses of co-trimoxazole. In addition, delayed hypersensitivity rashes can occur; all these need to be monitored by the pharmacist to ensure the medicines prescribed are just as appropriate and safe for the patient as the day they were prescribed.

I agree that hospital may not be the best place to initiate smoking cessation, especially if a patient has to deal with an HIV diagnosis and life-long medication. Although this patient has recently cut down on the number of cigarettes smoked, NHS smoking cessation advice is that cutting down is not an effective strategy for health benefits. Smokers who cut back are said to draw more deeply and smoke more of each cigarette so potentially still get the same dose of toxic tobacco smoke with fewer cigarettes, which can affect lung recovery rates and function. As the pharmacist I would endorse the “to take away” (TTA) discharge letter recommending an active smoking cessation programme post discharge with the GP or community pharmacy. 

Key points

  • Pneumocystis pneumonia (PCP) is an opportunistic fungal infection that can cause respiratory failure. Around 90 per cent of cases occur in HIV patients.
  • HIV patients with CD4 counts <200cells/mm3 should be given prophylaxis — co-trimoxazole is recommended. This drug is also used as first-line treatment.
  • Early use of steroids has been shown to reduce mortality in moderate to severe cases.
  • About 50 per cent of people treated with co-trimoxazole experience side effects. These commonly include rashes, headache, nausea, diarrhoea, leukopenia and hepatic inflammation.
  • One of the key contributions that pharmacists can make in the care of patients with PCP is to be proactive in monitoring for drug toxicity.

Resources

Further information on PCP and other opportunistic infections is available at www.bhiva.org

About the author

Lucy Hedley PgDipGpp, MRPharmS, is a rotational clinical pharmacist at UCLH NHS Foundation Trust

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11120728

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