N BELL & A WHITTLE 208 Further reading Abramson S. The Air Crescent Sign. Radiology 2001; 218: 230 \200\223232. Ko the H, Dalhoff K. Pneumonia in the immunocompromised Ra a A, Agust a C, Jimeneza P, et al. Pulmonary in \201 ltrates in non-HIV immunocompr omised patients: a diagnostic approach using non-invasive and bronchoscopic procedures. Tho rax 2001; 56: 379 \200\223387. patient. Eur Respir Mon 2006; 36: 200 \200\223213. Shellito J. Symposium: The Compromised Host. Proc Am Thoracic Kotloff RM, Ahya VN, Crawford SW. Pulmonary Complications of Solid Organ and Hematopoietic Stem Cell Transplantation. Am J Resp Crit Care Med 2004; 170: 22 \200\22348. Soc 2005; 2: 397 \200\223460. Pizzo PA. Fever in Immunocompromised Patients. New Engl J Med 1999; 336: 309 \200\223316. This page intentionally left blank A DUNLEAVY, M LIPMAN & R MILLER 210 9.2 Infection in the HIV compromised host Since the \201 rst, consistent reports of HIV infection in the early 1980s, the speed at which advances in our under- standing of this condition have taken place is unparalleled in medicine. The introduction of HAART in 1995, plus effective chemoprophylaxis against oppor tunistic infec- tions, has transformed the natural history of HIV infection from one with a uniformly gloomy outlook to a condition with an associated life-span perhaps not much less than that of the general population in the developed world. Despite this it remains a huge global health problem. For respiratory physicians this is important as the lungs are the s ite most commonly affected by opportunistic infections (OI). The UNAIDS estimated that in 2 007, 33.7 million individu- als were living with HIV infection. Two-thirds of these are wit hin sub-Saharan Africa. Approximately 21.5 million peo- ple have died since 1990 as a resul t of HIV infection. Possibly up to 50% of these have been due to TB. In the US there are ab out 1 million infected individuals; whilst the UK has around 72,000. Survey data suggest th at almost one third of these people do not know they are infected. Thus it is depressingly common to see patients presenting in extremis with undiagnosed HIV infection and opportun- istic disease. The major groups of affected individuals within the UK are men who have sex with other men (MSM) (40% of cases), heterosexual women (30%), heterosexual men (20%) and i njecting drug users (<5%). New cases are more frequently heterosexual than MSM; and are fou r times more likely to be black-African than any other ethnic group. This chapter describes respiratory infections in individuals with known or suspected HIV infection. It provides a gen- eral approach to assessment, and then covers speci \201 c, important pulmonary infec tions relevant to UK practice. Table 9.2.1 Causes of pulmonary infection in the HIV compromised Bacterial Streptococcus pneumoniae Haemophilus in \202 uenzae Staphylococcus aureus Pseudo monas aeruginosa Escherichia coli Mycobacteria Mycobacterium tuberculosis Mycobacterium avium-intracellulare complex Mycobact erium kansasii Other non-tuberculous mycobacteria Fungi Pneumocystis jirovecii Cryptococcus neoformans Histoplasma capsulatum Penicillium mar neffei Aspergillus spp. Coccidioides immitis Blastomycetes dermatitidis Parasites Toxoplasma gondii Strongyloides stercoralis Viruses Cytomegalovirus Adenovirus Herpes simplex is >200 cells/ l, bacterial pneumonia and TB are most likely. At lower CD4 counts, PCP, fu ngal and non-tuberculous mycobacterial infections are additional possibilities. It should b e remembered that PCP can occur at higher CD4 counts (especially in people with physical in dicators of immune suppression such as oral thrush; or very high HIV plasma loads). It may also be seen occasionally during acute (primary) HIV infection when there is a profound, tr ansient fall in systemic immunity. Blood CD4 counts may \202 uctuate on a day to day basi s; and it can be helpful to also know either the CD4:CD8 ratio or CD4 percentage (of all T and B lymphocytes), which are rather more stable measures. The latter can be related to blo od CD4 absolute counts if one remembers that a CD4 of 200 cells/ l is usually 14%, and CD4 of 400 cells/ l is roughly double that at 27%. General approach to the HIV patient with pulmonary infection The immune dysregulation assoc iated with HIV means that a wide spectrum of organisms may be responsible for pul- monary i nfection (Table 9.2.1). However, it is important to remember that Pneumocystis jirovecii pn eumonia (PCP) and bacterial pneumonia are the commonest causes of acute, life-threatening H IV-related respirator y disease. Mycobacteria (and in particular TB) should not be forgot- ten; nor that more than one pathogen can be demon- strated in up to 20% of cases. Although there may be helpful pointers in the history, examination and initial sim- ple investigatio ns, often the decision needs to be taken to start empiric therapy prior to obtaining a de \201 nitive diagno- sis. This is discussed in more detail later in this chapter. Important points in assessment The degree of immunosuppression It is possible to map speci \201 c respiratory conditions to the level of an individual \200\231s immuno-suppression. This is most easily assessed using blood CD4 T-lymphocyte counts, which generally are inver sely related to the degree of immune dysfunction. In an HIV-uninfected individual the norma l absolute CD4 count is between 500 \200\2231500 cells/ l. During the course of untreated HIV infection this will almost certainly fall to near undetectable levels after sev- eral y ears. Different organisms should be considered depending on the blood CD4 count. When the C D4 count Patient medication history Patients who are using effective HAART (sustained sup- pression or near-suppression of plasma HIV load for at least 3 months) have a greatly reduced (50 \200\22380%) risk of severe respiratory illness. This is particularly the case for PCP and TB; though rather less so with bacterial pneumo- nia. The use of speci \201 c OI prophylax is (such as PCP proph- ylaxis with co-trimoxazole taken at an effective dose for at least 2 weeks) is also relevant; as this may suggest alterna- tive diagnoses (than in this example , PCP) or raise the pos- sibility of the development of resistance to the prophylactic agen ts. Medication (e.g. the antiretroviral, zidovudine or CHAPTER 9.2 Infection in the HIV compromised host 211 Investigations Serology. Pneumococcal urinary antigen is helpful in sus- pected bacterial p neumonia. It has a similar sensitivity (approaching 80%) and speci \201 city (approximatel y 95%) in HIV infected and uninfected individuals. Urine testing for Legionella antigen may also be of value; whilst in appropriate cases, urine and blood Histoplasma polysaccharide antigen tests have good sensitivity; although false positives can occur in Blastomyces and Coccidioides spp. infected individu- als. Serum cryptococcal antigen has excellent speci \201 city; though is less sensitive in local (e.g. pulmonary) cryptococ- cal infection than in disseminated disease, where crypoto- coccaemia is more likely to be present (e.g. >90% positive in cryptococcal meningitis). Serology (acute and convales- cent) can be sent for a typical organisms such as Legionella pneumophila, Mycoplasma pneumonia and Chlamydia spp. L actate dehydrogenase (LDH) is elevated in up to 90% of patients with PCP; however it is als o increased in several other infections (in particular mycobacterial disease and histoplasm osis) as well as lymphoma and lymphocytic interstitial pneumonitis (LIP). As such it lacks diagnostic speci \201 city. prolonged use of antibiotics such as rifabutin) can lead to neutropenia and a subsequent in creased risk of systemic bacterial infections and invasive fungal infections Mode of infection Injecting drug users are at greater risk of bacterial pneu- monia and TB. Travel, residence and ethnic origin PCP is found more frequently in European and US studies than those from the developing world, where TB and bac- terial pneumonia predominate. Howe ver patients who have previously lived in TB-endemic areas are inevitably at a much greater risk of active TB when resident in the West than the native populations. Reactivation of c ertain other conditions should also be considered in individuals who have lived or traveled to certain parts of the world. These include fungi such as Histoplasma capsulatum (the Ame ricas, Africa and many parts of Asia), Coccidioides immitis and Blastomyces dermatitidis (p redominantly the Americas and Africa), Penicillium marneffei (South-East Asia) and worm inf ections including Strongyloides stercoralis (same distribu- tion as Histoplasma). A history of previous PCP or TB increases the likelihood of recurrent infection. Recurrent bacterial infection may lead to bronchiectasis; which in turn will promote further acute respiratory disease with the types of organisms usually associated with this condition. Non-infectious diagnoses should also be considered. These will be discussed in Chapter 9.3. Blood cultures The increased rates of bacteraemia and septicaemia in HIV-related bacterial pneumonia mean that blood cultures are reported to be positive 40 times more frequently tha n found in HIV-negative controls. It is important that good - quality blood cultures for bo th bacteria and mycobacteria (where appropriate) are obtained. Exercise oxygen saturation. Transcutaneous oximetry may be used in HIV-infected patients to assess for exercise- induce d oxygen desaturation. This is of most value in discriminating subjects with a \201 rst e pisode of PCP and nor- mal or near normal chest radiographs, from other causes of this clin ical picture. It is generally regarded as a fall to less than 90% from a baseline of \211 95%, following exercise which increases heart rate towards 80% of predicted maximum. Arteri al blood gas analysis provides more information than oxygen saturations. For a given severi ty of clinical disease a wider arterial oxygen gradient (A \200\223aO2) is found in those w ith PCP or other causes of alveolitis compared to bacte- rial pneumonia. Fewer than 10% of patients with PCP have a normal PaO2 and a normal A \200\223aO2. Lung function testing may con \201 rm decreases in gas transfer, DLCO, which mirror exercise desaturation in those w ith PCP. However it is not a test which can distinguish between the different underlying ae tiologies of a given clinical pic- ture \200\223 and is therefore of little diagnostic val ue. CXR may show focal areas of consolidation, diffuse in \201 ltrates, nodules or pneumot horax. The radiological pattern may be helpful as shown in Table 9.2.2. CT scanning of the chest and mediastinum may be useful when the CXR is normal or equivocal. HRCT may reveal th e typical ground-glass appearance of an alveolitis that is often found in PCP. However the features lack speci \201 city for this condition. It may also aid in the diagnosis of non- infectious causes such as pulmonary embolism, idiopathic pneumonitis and lymphocytic inters titial pneumonitis. HRCT can also aid in guiding a more directed BAL. Mediastinal imaging m ay reveal unsuspected lymphadenopathy. Central necrosis of these nodes is usually regarded as indicating either mycobacterial or, less commonly, fungal disease or IRIS (immune recons titu- tion in \202 ammatory syndrome). Clinical features Systemic symptoms such as fever, weight loss, and fatigue are present to a variable extent in many respiratory infec- tions. In themselves, therefore, they may prov ide little additional diagnostic information. Progressive breathlessness (usually worsening over the space of several days to weeks) is regarded as characteris- tic of PCP. A pattern of sudden deterioration on a gradual background may result from pneumothorax (which again is typically associated with PCP). Cough with sputum is suggestive of bacterial pneumonia o r mycobacterial disease. Dry cough of gradual onset is more indicative of PCP in a patient with a CD4 count <200 cells/ l. Although community acquired viral pneumonias (e.g. in \202 uenza A) do not appear to be any more common in HIV infected subjects, they will be mi ssed if not actively sought. In presentation they often mimic PCP. Haemoptysis is suggestiv e of mycobacterial or fungal causes. Pleuritic chest pain can occur in all infections but i s more commonly noted with bacterial pneumonia. Pleural effusions may be found in any patie nt with pneumo- nia but are more commonly associated with bacterial (small to medium size), mycobacterial (any size) infections; malnutrition, renal impairment, \202 uid overload ( small and bilateral) or malignancy (including lung cancer, primary effusion lymphoma and Ka posi sarcoma). They are rare in PCP. Hepatosplenomegaly can be found in disseminated myco- bacterial or fungal disease, lymphoma or multicentric Castleman disease (angio-follicular h yperplasia). Lymphadenopathy is suggestive of similar diseases, though smooth, non-tender a nd symmetrical nodes in the neck, axillae and groin are present in many asymptomatic HIV- i nfected individuals who are not receiving HAART. A DUNLEAVY, M LIPMAN & R MILLER 212 Table 9.2.2 Common chest radiograph \201 ndings in the HIV-infected individual Induced sputum (IS) may be more helpful, as spontaneous sputum samples are inadequate for t he routine diagnosis of PCP. Here, samples are obtained by inhaling hypertonic saline via a n ultrasonic nebuliser. Given the possible risk of nosocomial aerosol transmission of e.g. TB, IS should be performed in a well-ventilated setting or a negative- pressure environment , away from other patients. The sen- sitivity of induced sputum for PCP varies markedly (be tween 50 \200\22395%). This probably re \202 ects the degree of local experience in both s putum sample production and interpretation. Thus, a negative test result from IS should pro mpt further investigations \200\223 typically bronchoscopy and BAL. Once the sample is in the laboratory, immuno \202 oures- ence staining enhances yield when compared to standard Grocott silver staining. IS is also helpful in patients with suspected TB who are either sp ontaneous sputum smear negative or not producing sputum. In such patients IS has a similar yield to bronchoscopy and BAL. Bronchoscopy allows airway and alveolar sampling, as well as direct visualization of the proximal airways. In the latter case it is of more assistance in the diagnosis of non-infec- tive complications discussed in the next chapter in known or suspected HIV infected. A good quality BAL (composed of mainly alveolar cells with few bro nchial epithelial cells) should be obtained and analyzed for bacteria, mycobacte- ria, viru ses, fungi and protozoa. Pneumocystis jirovecii cannot be cultured. Therefore histochemical examination for this organism is important (see earlier in chapter). BAL has a sensitivity of around 90% for Pneumocystis jirovecii. BAL is also helpful in suspected fungal pneumoni a; where the organism may be detected with antigen testing e.g. Cryptococcus antigen. Trans bronchial biopsy (TBB) is usually reserved for patients in whom other investigations have f ailed to provide a diag- nosis. The sensitivity of TBB for PCP is up to 90% when used as th e sole diagnostic test. It is greater than 95% when combined with BAL. However there is a r elatively high complication rate with an increased risk of pneumothorax or pulmonary hemorr hage. Chest radiological \201 nding Diagnosis Normal Pneumocystis pneumonia (PCP) Viruses TB Focal in \201 ltrate Bacteria (S.pneumoniae, H. in \202 uenzae) Mycobacteria Fungi (Cryptococcus, Histoplasma, Aspergillus, Coccidioides) Complex bacteria e.g. Nocardia Pulmonary Kaposi \200\231s sarcoma or lymphoma PCP (an apical in \201 ltrate if on prophylactic nebulised pentamidine) Diffuse in \201 ltrate PCP (classical presentation) Mycobacteria Respiratory viruses CMV Bacteria Fungi Toxoplasma Lymphocytic interstitial pneumonia Non-speci \201 c interstitial pneumonia Diffuse nodules Mycobacteria Fungi (small nodules) Kaposi \200\231s sarcoma, lymphoma (large nodules) Cavities Bacteria (S. aureus, S.pneumoniae Klebsiella) TB, M. kansasii Fungi PCP may appear to cavitate if pneumatoceles present Overall management approach A balance needs to be sought between obtaining a de \201 ni- t ive diagnosis and treating empirically for the likeliest path- ogens (which may be multiple ). If the patient is sick, treatment should be instituted for what is often bacterial pneum onia, PCP or mycobacterial disease. In this situation, investigations need to be tailored t o what is practicable, though without speci \201 c pulmonary samples it may be dif \201 c ult to obtain a \201 nal diagnosis. Pleural effusion Bacterial TB Primary effusion lymphoma Lung cancer Pneumothorax PCP Mycobacteria Mediastinal adenopathy Tuberculosis Non-invasive ventilation and intensive care Respiratory support with e.g. CPAP can be initi ated in those with evidence of hypoxia and no hypercapnia. Patients who require ICU admissi on for pulmonary infec- tions are often those who are presenting with a \201 rst severe H IV-related illness. With the improvement in treatment of OI and the bene \201 ts of HAART, HIV-infected individuals should not be excluded from full ventilatory assistance if deemed appropriate. Recent studies suggest that overall survival from ICU is similar to that of a non-infected population at greater than 65%. In general unless a patient has a clear cut-t erminal illness (e.g. lymphoma unrespon- sive to therapy), they should be offered admission and comprehensive ICU care. One also needs to consider other co-morbidities, as well as th e wishes of the patient when reaching a decision about this. Prognostic factors Other mycobacteria Fungi Kaposi \200\231s sarcoma Lymphoma Castleman \200\231s disease Microbiology. All patients who are expectorating sputum spontaneously should have samples s ent for Gram stain, culture and sensitivity together with samples for staining for acid-fas t bacilli and mycobacterial culture. Ideally early morning (or overnight) specimens should be sent on 3 separate occasions to maximize diagnostic sensitivity for mycobacteria. CHAPTER 9.2 Infection in the HIV compromised host 213 that appear to carry a worse outcome for HIV positive patients admitted to ICU include lowe r hemoglobin, lower blood CD4 count, higher APACHE II score and need for mechanical ventila tion. The largest single group of patients who require ICU admission will have PCP. Here fu rther factors associated with mortality include increasing age, the presence of pneumothora x and mechanical venti- lation with a strategy which does not use low tidal vol- umes. The latter is especially interesting as unlike the majority of other prognostic factors, this c an be in \202 uenced favorably during the ICU admission itself. Treatment for the presumed or con \201 rmed causative organisms should be based on local g uidelines and resist- ance patterns. In practice it is often sensible to treat with a broad spectrum antibiotic such as co-amoxiclav or a \200\230second \200\231 or \200\230third \200\231 generation cephalosporin in the \201 rst instance, even if PCP is suspected. Pneumocystis jirovecii pneumonia P. jirovecii (formerly called P. carinii) is a fungus that causes infection speci \201 c to humans. To avoid confusion, the term PCP remains to desc ribe PneumoCystis Pneumonia. Serology shows that most people have been exposed to Pneumocys tis in childhood. However latest evidence suggests that re- infection is the main source of clinical disease. Evidence for nosocomial transmission exists but is limited. Before the a dvent of prophylactic therapy and HAART, PCP occurred in up to 80% of HIV-infected individu als with AIDS and was the \201 rst OI described in this context. PCP is now much less com mon and is seen mainly in individuals of unknown or undisclosed HIV status; or HIV-infected individuals not using adequate PCP prophylaxis or HAART (see later). PCP has been reported from all parts of the world. Immune reconstitution in \202 ammatory syndrome (IRIS) This intriguing condition was origi nally noted in the con- text of treatment for HIV negative mycobacterial disease several ye ars ago, where subjects on effective therapy would have a paradoxical deterioration in thei r symptoms following an early initial improvement. It is thought to be the clinical manifes tation of a returning immune response directed against speci \201 c antigen. IRIS will be discussed in more detail in the chapter on non-infectious respiratory complications of HIV infection, though is most commonly reported (in up to one-third) of HIV patients with syste mic mycobacterial or fungal infections who start HAART. There is no diagnostic test for IRI S; and it should only be accepted as the cause of symptoms when other possibilities such as drug failure (due to resistance, non-adherence or adverse effects) or new opportunistic di seases have been excluded. Clinical presentation Almost 90% of cases occur in HIV-infected persons with blood CD4 T-ce ll counts <200 cells/ l (or a CD4 T-cell percentage <14%). Other risk factors for disease in sub- jects not receiving effective HAART include oral candidia- sis, oral hairy leukopla kia, unintentional weight loss, recurrent bacterial pneumonia, previous PCP and high plasma HIV load. The most common presentation is with gradually progressive exertional dyspnoea, malaise and a dry cough. However, there may be a wide variety of respi- ratory symptoms. Th ere is often little to \201 nd on examina- tion, although there may be some \201 ne ins piratory crackles audible at the lung bases. Radiological \201 ndings are described in Ta ble 9.2.2. Speci \201 c infections Bacterial pneumonia Bacterial pneumonia occurs two to four times m ore fre- quently in HIV-infected individuals than the general popula- tion. Risk factors in clude previous pneumonia, injecting drug use, cigarette smoking and declining CD4 count. Th e clinical presentation, assessment and treatment are broadly similar to that of non-HIV in fected individuals, as discussed in Chapter 9.1. The most common pathogens in the gen- eral population are also largely those encountered in HIV infected subjects. The key difference s and special consid- erations in the HIV-infected patient are outlined. \200 Diagnosis The use of transcutaneous oximetry to assess for exercise induced desaturation ha s been validated in the case of PCP with normal or near normal CXR. Patients with a given s everity of disease have a wider arterial oxygen gradient (A \200\223aO2) than other causes of pulmonary infection. Radiological \201 ndings (Table 9.2.2) may be of assistance. De \201 nitive diagnosis requires identi \201 cation of the organism either by silver or immu no \202 ourescence staining from pul- monary secretions or tissue. Molecular ampli \201 c ation meth- ods of detection are not routinely used, though early studies using upper and l ower respiratory tract specimens suggest they may be helpful. Empiric treatment vs bronchos copy \200\223 debate exists regard- ing whether or not a de \201 nitive diagnosis is requ ired. The controversy arises from the high frequency of PCP found in the pre HAART era \200\223 and hence the good positive predic- tive value of compatible symptoms in patients with a CD4 count of <200 cells/ l. However as PCP has become less common, so symptoms are less predictive of PCP; and it is advisable that diagnosis should now be actively sought. T his is further supported by the following: (1) 20% of HIV- infected patients presenting wit h respiratory symptoms who are thought to have PCP do not have this diagnosis; (2) response to treatment of PCP typically takes 4 \200\2237 days. Thus, if the diagnosis is incorrect the patient may have had increased time on potentially toxic drugs; (3) if empiric treatmen t fails, one may need to consider bronchoscopy at a point when the patient is more unwell a nd therefore at Bacteraemia is up to 100 times more common with a diagnostic rate of blood culture being 40 -times that of HIV-uninfected patients. CXR may be atypical with diffuse in \201 ltrates p resent in up to 50%. Lobar or segmental consolidation may result from a wide variety of bac terial, mycobacterial, fungal and viral pathogens. Pleural effusions occur twice as often a nd empyema and pleural abscess are also seen more frequently. As the CD4 count falls to <20 0 cells/ l more unusual organisms are implicated. These include Staphylococcus aureus and Pseudomonas aeruginosa. Nocardia asteroides infection can occur at low CD4 counts although the use of trimethoprim/sulfamethoxa- zole (TMP-SMX, co-trimoxazole) as PCP prophylaxis may have decreased its overall incidence. Diagnosis is made by identi \201 cation of the orga nism in sputum or BAL. Rhodococcus equi can occur in subjects with very low CD4 counts who have a history of exposure to farms and farm animals. Identi \201 cation of the organism b y cul- ture of sputum, BAL or blood is diagnostic. A DUNLEAVY, M LIPMAN & R MILLER 214 greater risk of complications including post-bronchsocopy deterioration; (4) there is frequ ently more than one patho- gen present \200\223 and BAL specimens may provide information about this. four divided doses for three days, followed by 90mg/kg/day intravenously for the remaining 18 days. This strategy appears to be equally ef \201 cacious as giving the higher dose for 21 days, but has a lower incidence of bone marrow disturbance. The dif \201 culties of gi ving prolonged intrave- nous therapy means that many clinicians will switch patients who de monstrate a good and sustained response to oral from intravenous therapy after approximatel y a week. in mild-moderate disease either co-trimoxazole 1920mg orally three times daily fo r 21 days or the IV regimen can be given. Second-line agents. Current evidence suggests lit tle differ- ence in ef \201 cacy for the recommended second-line agents and the choice of regimen is often determined by patient tolerance and the ability to take oral or IV medicat ion. There should be a treatment crossover period of 48 hours unless toxicity to the \201 rst-line agent has developed. Expert advice should be sought in patients who are failing t o respond. Clindamycin and primaquine in combination has a better tox- icity pro \201 le t han IV pentamidine. This makes it a preferable second-line agent, where it is effective in approximately 70% of patients. Methaemoglobinemia due to primaquine occurs in up to 40% of patients. However this can be reduced if pri- maquine 15mg once daily is used in place of 3 0mg once daily. Diarrhea is common on clindamycin and if it develops stool samples should b e sent for Clostridium dif \201 cile toxin. Trimethoprim \200\223 dapsone is an appropria te option for mild- moderate PCP. Asymptomatic methaemoglobinemia occurs in the majority of patients (secondary to dapsone). Approximately 50% will develop mild hyperkalaemia seconda ry to trimethoprim. This drug combination is tol- erated in approximately one-third of pati ents who have developed late, non-severe but persistent rash with co- trimoxazole. Intraven ous pentamidine is mainly reserved for those with severe disease in whom there has been the rapeutic failure on co-trimoxazole. Nephrotoxicity, hypotension, leucopenia, Management On the basis of clinical \201 ndings and prior to commencing treatment, the se verity of PCP can be strati \201 ed into mild, moderate and severe disease (Table 9.2.3). This categoriza- tion can assist clinicians in their choice of appropriate drugs with prove n ef \201 cacy. These are outlined in Tables 9.2.3 and 9.2.4. On the basis of an NIH Conse nsus Statement con- current adjuvant glucocorticoid therapy is advocated in those with mode rate or severe pneumonia (Table 9.2.3). The bene \201 t has been demonstrated if glucocort icoids are started within 72 hours of speci \201 c anti-PCP therapy. It should be noted th at co-trimoxazole, dapsone, and pri- maquine must not be given in glucose-6-phosphate dehy- drogenase deficient patients as they are at risk of haemolysis. Thus, levels should be che cked prior to com- mencing treatment. Co-trimoxazole for 21 days is \201 rst-line treatme nt for HIV- patients with PCP regardless of severity provided there are no contraindication s. This regimen is effective in up to 90% of patients with mild disease and in 70% of those with severe pneumonia. Adverse reactions to co-trimoxazole are common and usually become a pparent between days 6 and 14 of treatment. Neutropenia and anemia, rash (which may be seve re), fever and abnormal liver function tests occur most frequently. Patients receiving co-t rimoxazole should be monitored with full blood count, liver function, and urea and electrol ytes at least twice weekly. HIV- infected individuals have higher rates of adverse reaction s on cotrimoxazole; the reason for this is unclear. If minor, rash can often be managed wit h the use of systemic antihistamines and careful monitoring to ensure no deteri- oration oc curs. Individuals with moderate to severe disease (Table 9.2.3) should be given 120mg/kg/da y intravenously in three to Table 9.2.3 Strati \201 cation of disease severity in PCP Mild Moderate Severe Dyspnoea and tachypnoea at rest; persistent fever and cough Symptoms and signs Dyspnoea on exertion with or without cough and sweats Dyspnoea on minimal exertion and occasionally at rest; cough and fever >11.0 (>83) 8.1 \200\22311.0 (61 \200\22383) \211 8.0 ( \211 60) Oxygenation PaO2 room air, at rest in kPa (mmHg) >96 91 \200\22396 <91 SaO2, at rest on air PAO2-PaO2* in kPa (mmHg) CXR <4.7 (<35) 4.7 \200\2236.0 (35 \200\22345) >6.0 (>45) Normal or minor peri-hilar shadowing Diffuse interstitial shadowing Extensive interstitial shadowing with or without diffuse alveolar shadowing First-choice treatment Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole Second-choice treatment Clindamycin-primaquine Clindamycin-primaquine Clindamycin-Primaquine or intravenous pentamidine Trimethoprim-dapsone Trimethoprim-dapsone Third-choice treatment Atovaquone Intravenous pentamidine Fourth choice Intravenous Atovaquone CHAPTER 9.2 Infection in the HIV compromised host 215 Diagnosis TB diagnosis relies on a similar approach to that used in HIV- uninfected subject s. Samples for AFB smear and culture should always be obtained. If a patient is producing s putum then this should be examined for acid fast bacilli. Although this is less likely to b e positive than in HIV- negative subjects, blood, urine and bone marrow cultures are more f requently diagnostic. The tuberculin skin test (which relies on good cell-mediated immunity ) is of fairly limited value in co-infected patients, especially in those with a blood CD4 count below 200 cells/ l. pancreatitis and hypo- or hyper-glycemia are relatively common. The long half-life of penta midine means that adverse effects may arise at any time (even several days or weeks after t he drug has been discontinued). Further support. CPAP can be helpful in hypoxic patients an d may avoid the need for mechanical ventilation. This is especially helpful in the \201 r st few days of therapy; or if the patient deteriorates post-bronchoscopy. Failure to respon d to apparently \200\230appropriate \200\231 treatment may result from a number of factors ; which should be carefully sought and excluded. These are summarized in Table 9.2.4. Treatment Drugs. Standard \200\230four drug \200\231 treatment with a rifamycin (usually e ither rifampicin or rifabutin), plus isoniazid, pyrazi- namide and ethambutol for two month s followed by con- solidation with rifamycin and isoniazid is the treatment of choice for d rug sensitive disease. Vitamin B6 (10 \200\22325mg once daily) is usually also given to pro tect against isoniazid- induced peripheral neuropathy. Six months \200\231 treatment is adv ocated for most patients; though should be prolonged to nine months in those with cavitator y pulmonary disease, or positive cultures after two months \200\231 treatment where the org anism is known to be drug sensitive and patient adherence is very good. The prolonged durat ion of therapy is designed to reduce the higher risk of relapse that has been reported in t hese sub-groups. Treatment adverse events are common. Moderate to severe rash, hepatotox- i city or gastro-intestinal disturbance occurs in up to 40% of co-infected subjects. This is in part due to the overlapping toxicities with HAART. The best example of this is the perip heral neuropathy that will almost certainly result if isoniazid is given together with the nucleoside reverse transcriptase inhibitor stavudine. Mycobacterium tuberculosis As a genuine and global pathogen, TB can present in all HIV infe cted individuals at any stage of HIV infection. The T cell defects associated with HIV mean that the chance of an individual who has latent TB infection progressing to active clinica l disease is 50 \200\223100 times greater than background rates in HIV negative subjects. T his translates roughly as a reactivation rate of 5% per year compared to a lifetime risk of 5% in HIV-negative individuals. Clinical presentation Patients with higher CD4 counts (>350 cells/ l) present in a similar manner to HIV-negative patients with TB. The immune dysregulation associated with falling blood CD4 counts means that as the CD4 count drops to below 200 cells/ l, patients are mor e likely to have non-pulmonary, disseminated and multi-organ disease. Pulmonary manifes- ta tions are also often different at low blood CD4 counts. \200\230Typical \200\231 chest rad iographic cavitation is replaced by pulmonary in \201 ltration, pleural effusions and medi astinal lymphadenopathy, Table 9.2.4 Treatment schedules for Pneumocystis jirovecii pneumonia Drug Dosage Notes Use in moderate to severe PCP Dilute 1:25 in 0.9% saline infused over 90 \200\223120 minute s Trimethoprim- sulfamethoxazole Trimethoprim 20mg/kg IV q24h and sulfamethoxazole 100mg/kg IV q24h in 2 \200\2233 divided d oses for 3 days then reduced to trimethoprim 15mg/kg IV q24h and sulfamethoxazole 75mg/kg I V q24h in 2 \200\2233 divided doses for 18 further days Same daily doses of trimethoprim-sulphamethoazole PO q24h, in 3 divided doses for 21 days Use in mild to moderate PCP 1920mg (2 trimethoprim-sulphamethoxazole double strength tablets) PO q8h for 21 days Clindamycin- primaquine Clindamycin 600 \200\223900mg IV q6h or q8h IV and primaquine 15 \200\22330mg PO q24h for 2 1 days Methaemoglobinemia Less likely if dose of 15mg PO q24h of primaquine is used Clindamycin 300 \200\223450mg PO q6h to q8h and primaquine 15 \200\22330mg PO q24h for 21 d ays Pentamidine 4mg/kg IV q24h for 21 days Dilute in 250mL 5% dextrose in water and infuse over 60 minutes Trimethoprim- dapsone Trimethoprim 20mg/kg PO q24h in 3 divided doses and dapsone 100mg PO q24h for 21 days Atovaquone 750mg PO q12h for 21 days Give with food to increase absorption Prednisolone 40mg PO q12h, days 1 \200\2235 40mg PO q24h, days 6 \200\22310 20mg PO q24h, days 11 \200 \22321 Start corticosteroid as soon as possible and within 72 hrs of commencing speci \201 c anti -PCP treatment, if PaO2 <9.3 kPa (<70 mmHg) Methylprednisolone IV at 75% of dose given above for prednisolone A DUNLEAVY, M LIPMAN & R MILLER 216 Treatment Treat with either IV liposomal amphotericin and \202 ucyto- sine in meningitis and disseminated disease; or high dose \202 uconazole if there is more limited pulmonary disease. Generally, HAART should be commenced as soon as pos- sible, though IRIS may be mor e likely if HAART is started early. Drug-drug interactions are common in HIV patients with TB. One of the main pharmacokinetic areas of concern is that between rifamycins and antiretroviral drugs. Rifampicin is a poten t inducer of the cytochrome P-450 system. Non- nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PI) are metabolized using cytochrome P-450. Thus reduced concentrations of the NNRTIs and PIs and the development of resistance to HIV can occur if used in combination with rifampicin. Rifabutin is a less potent inducer of the cytochrome P -450 system, but is also a sub- strate of the same enzyme. Hence drugs such as PIs which in hibit the cytochrome P-450 system will lead to increased serum concentrations of rifabutin. Although there are lim- ited clinical trial data with this drug, most clinicians feel that it is as effective as rifampicin when treating TB. Timing of commencing HAART. The \201 rst priority for the TB/HIV co-infected patient is to treat TB. The optimal time to start r emains unclear. A suggested approach is (1) in those with a CD4 count of >200 cells/ l to withhold HAART for the duration of TB treatment; (2) in those with a CD4 count <200 cells/ l but >100 cells/ l to delay HAART until the patient is established on anti-TB therapy (u sually up to two months); (3) to start HAART as soon as possible in those with a CD4 count of <100 cells/ l (usually after about two weeks, based on physician assessment). Drug resi stance is twice as common in HIV co-infected individuals. Multi drug resistance and XDR (ex tremely drug resistant) TB is an increasing global problem. This is likely to be due to rap id progression from latent to active infec- tion combined with delayed diagnosis of disease through atypical presentation. IRIS is commonly associated with TB. Its diagnosis and mana gement is discussed in more detail in the next chapter. Aspergillosis Aspergillosis is relatively rare in HIV-infected individuals compared to thos e with severe immunocompromise from other causes. It is usually seen in the context of prof ound immunosuppression (blood CD4 counts <50 cells/ l). This may also be associated with n eutropenia from drugs such as co-trimoxazole or zidovudine; or the use of systemic glucocor ticoids. Diagnosis rests on the clinical picture plus radiology with or without identi \201 cation of aspergillus from lung specimens. The diagnostic utility of measuring galacto - mannan in blood or lung has not yet been de \201 ned in the HIV-infected patients. Treat ment is similar to that used in other patients, with either voriconazole or liposomal ampho tericin B being \201 rst choice therapies. Candida Candidal infection of the trachea, bronchi and lungs is rare in HIV-infected indivi duals. Although isolation of candida in the sputum is common it usually represents coloniza tion of the oropharynx. Endemic fungi Histoplasma, Coccidioides, Blastomycoses, Paracoccidioides, and Penicillium i nfection are rare in the UK; though should be considered in patients with signi \201 cant immunosuppres- sion who have spent time in parts of the world where these fungi are endemic (see earlier in chapter). The typical presentation is with disseminated disease rather tha n iso- lated pulmonary infection. Just as with cryptococcal infec- tion, patients may have a variety of skin lesions present. These will often be culture positive if biopsied. Treatm ent should be undertaken with specialist input, though in an emergency, IV amphotericin B w ill be effective.