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Pneumocystis carinii Pneumonia in Diabetic Patient

Marques, S.; Marcelino, P.; Martins Baptista, A.; Aldomiro, F.; Ribeiro, J.; Malhado, J.

Infectious Diseases in Clinical Practice: November 2002 - Volume 11 - Issue 8 - p 441-444
doi: 10.1097/01.idc.0000086409.30743.9f
Original Article
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Pneumocystis carinii pneumonia (PCP) is an opportunistic infection, most frequently associated with the human immunodeficiency virus (HIV). It is seldom described in patients who are HIV negative, but PCP has been described in patients with a depression in their immune system secondary to neoplasm’s, immunosuppressive therapy, or in the context of primary immunodeficiency—in all these cases a low CD4+ lymphocyte count was confirmed.

The authors present the case of a 46-year-old male Caucasian patient with a confirmed diagnosis of PCP in whom all possible causes of depression of the immune system were excluded, including primary immunodeficiency, immunosuppressive therapy, neoplasm, and HIV infection.

Address correspondence and reprint requests to: Sandra Marques, MD, Estrada das Biscoiteiras no. 8, 10 Dto., 2975-038 Linda-a-Velha, Portugal. E-mail: sandra.marques@create.pt

Pneumocystis carinii is an opportunistic eukaryotic pathogen that can cause life-threatening pneumonia in immunosuppressed patients. This clinical entity is most frequently described in patients who are HIV positive and who have CD4+ lymphocyte cell counts below 200 cells/mL, but P. carinii pneumonia (PCP) can be found in HIV negative patients. In the latter cases, the patients have a history of either solid tumors, hematological malignancies, organ transplantation, or chronic inflammatory disease, with the common denominator being a history of immunosuppressive therapy—systemic corticosteroid therapy is the most frequently described in these cases. 1,2

P. carinii was first identified by Carlos Chagas in 1909, but the clinical relevance of this pathogen only became evident during and after the Second World War. 2,3 While the genus Pneumocystis has been known to science for nearly a century, understanding of its members remained rudimentary until DNA analysis showed its extensive diversity. Pneumocystis organisms from different host species have very different DNA sequences, indicating multiple species. The organism that causes human PCP is now named Pneumocystis jiroveci Frenkel or currently P. carinii f. sp. hominis. 4

Classically, the patients most at risk for this opportunistic infection were children with serious malnutrition or primary defects in their immune system, patients with hematological malignancies (most frequently those with acute lymphoblastic leukemia) or organ transplant recipients (bone marrow or solid organs). 2 Other patients at risk for PCP are those with solid tumors and high dose systemic corticosteroid therapy, and those undergoing immunosuppressive therapy for chronic inflammatory disease. 1,2

Nowadays, the clinical presentation of this opportunistic infection varies with the presence or absence of HIV infection. In patients who are HIV positive, the clinical presentation is of a slowly progressive disease with nonspecific and mild signs and symptoms. In these cases, diagnosis is usually made only days to weeks after the appearance of symptoms. In HIV negative patients, the clinical presentation is of a rapidly evolving, serious, often life-threatening disease, with the need for mechanical ventilation in up to 27% of the cases. 2

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CASE HISTORY

A 47-year-old male Caucasian patient was admitted to our intensive care unit (ICU) with a diagnosis of life-threatening pneumonia, with serious hypoxemia, and in need of mechanical ventilation. The patient had a history of insulin-treated diabetes. He was not on other medication specially any corticosteroids in the last year, and there was no history of other clinical problems.

The patient was well until 2 days before being admitted to the hospital, when he presented with high grade fever (38-39°C), a dry nonproductive cough, and respiratory difficulty that got progressively worse. The initial physical examination revealed mental confusion, central cyanosis, and shortness of breath with the use of the intercostal muscles during inspiration. Pulmonary auscultation revealed rales over both pulmonary areas. The chest roentgenogram revealed bilateral diffuse infiltrates and the blood gas analysis revealed a serious hypoxemia (Table 1).

TABLE 1

TABLE 1

Owing to the severity of the hypoxemia (P O2 of 47 mm Hg), the patient was admitted to the intensive care unit where an endotracheal tube was placed and the patient was subjected to mechanical ventilation, with a partial improvement in the blood gas analysis. Treatment was initiated with ceftriaxone and clarithromycin, but no clinical or radiological improvement was observed. A chest CT scan, carried out 4 days after hospitalization, confirms a diffuse interstitial pneumonia and bronchoalveolar lavage led to the identification of P. carinii by a positive direct immunofluorescence test and using DNA amplification with nested PCR with oligonucleotide primers pAZ102-E and pAZ102-H designed for the P. carinii gene encoding the mitochondrial large subunit rRNA. After the pathogen had been identified, therapy was changed to co-trimoxazole and prednisone, with excellent clinical and radiological results. The clinical improvement was such that the patient was disconnected from the ventilator within 48 hours of the change in therapy. Treatment was continued for 21 days, with a progressive improvement; adequate control of glycemia during this period was difficult.

After the diagnosis of PCP was made, tests were carried out in an attempt to determine the level and the cause of an expected deficiency in the immune system. Serological testing for HIV, Mycoplasma pneumoniae, Chlamydea pneumoniae, Legionella spp, Coxiella burnetti, Toxoplasma gondii, Epstein-Barr Virus, human t cell leukemia types I and II, human herpes virus type 6, herpes simplex, and cytomegalovirus were all negative. CD4+ lymphocyte cell counts were persistently above 1000 cells/mL and HIV viral loads were persistently negative. Laboratory tests for chronic inflammatory diseases were all negative. In an attempt to identify a malignancy, a CT scan of the head, chest, abdomen, and pelvis was done, as well as gastrointestinal endoscopy (both esophagogastroduodenoscopy and colonoscopy), bone marrow aspirate, and bone biopsy, with the results of all these exams being normal. Ten days after being admitted to the intensive care unit, several immune function tests were carried out, namely, the study of neutrophil function in vitro, the measurement of serum immunoglobulin (Ig) levels, and Mantoux test. The neutrophil function was normal, and the levels of serum Ig was normal for all classes except for Ig A, which was found to be slightly elevated (568 mg/dL for an upper limit of 410 mg/dL). The Mantoux test was nonreactive.

On the 24th day of hospitalization, because quantitative lymphocyte tests were persistently normal, it was decided to carry out qualitative testing of lymphocyte function. The lymphocyte stimulation test, made with tritiated thymidine added to a culture medium of lymphocytes and antigen, was found to be highly diminished in their radioactivity, measured by a liquid scintillation counter—this reduction was confirmed in a second test. Three months later, the test was repeated, and this time, the results were normal.

The patient is now in his 8th month of follow-up, with good glycemic control and no further clinical events have been observed.

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DISCUSSION

PCP is an opportunistic infection that occurs when there is a major defect in cellular immunity, especially of the T lymphocytes. 3,5,6 This particular deficiency in the immune system is almost exclusively found in patients who are HIV positive or who are undergoing immunosuppressive therapy. Seroconversion to P. carinii usually occurs during early childhood, leading to high rates of seroprevalence—according to some authors, the rate of seroprevalence among the general population can be above 90%. 7 Although colonization in a healthy individual seems to be relatively frequent, progression to disease in an immunocompetent host is extremely rare. The presence of P. carinii DNA in sputum samples and bronchoalveolar lavage samples of immunocompetent individuals who came into contact with patients with PCP is transitory and self-limiting. 8 Recent studies have revealed that the colonization of the respiratory airways in immunocompetent patients with pulmonary disease is possible. 8 This observation suggests that lesion of the pulmonary tissues may facilitate the colonization with P. carinii8; however, the consequences of this colonization are minimal because as long as there is no deterioration in immune function, there is no progression to overt infection and pneumonia. 8,9

Before the HIV epidemic, the patients at risk for developing this rare but life-threatening pneumonia were severely undernourished infants, children with primary immunodeficiency syndromes, patients with hematological malignancies, and organ transplant recipients undergoing immunosuppressive therapy. Other patients at risk were those with solid tumors treated with high doses of corticosteroid therapy and those with chronic inflammatory diseases subjected to immunosuppressive therapy. 1–3,5–7

In the latter cases, the appearance of PCP during the steroid taper has been described; the reduction in corticosteroid dose may unmask the host inflammatory response to the pathogen. 2

The clinical presentation of PCP varies, depending on the presence or absence of HIV infection. 1,2P. carinii causes an acute, life-threatening pneumonia, with a high death rate among patients who are HIV negative, whereas in HIV positive patients, the clinical evolution is more insidious. 1 In the case described, the time between the initial complaints and the need for mechanical ventilation was approximately 72 hours. The fact that this patient had a history of diabetes does not seem to justify this rapid clinical evolution, as in patients with diabetes, the pneumonias caused by nonopportunistic pathogens have an insidious evolution, and the immunological deficiency responsible for this is an alteration in neutrophil function. In this case, the confirmation of PCP was made by a positive direct immunofluorescence and a PCR identification of the pathogen in the bronchoalveolar lavage. Both these diagnostic tests together have a sensitivity and specificity of 100%. 1,8,9

Although there are effective prophylactic and therapeutic options, the death rate in patients with PCP is high, with authors describing rates varying between 15% and 49%. 1,2 The higher death rates are found among HIV negative patients, 1,2 and for this reason, prophylaxis with co-trimoxazole in patients with immune deficiency or undergoing immunosuppressive therapy is becoming increasingly frequent. 1 In our patient, no prophylactic measures were taken as the alteration in the immune response was found to be temporary.

In the present case, a diagnosis of PCP was confirmed, and a transitory decrease in lymphocyte function was demonstrated by the lymphocyte activation or stimulation test. The lymphocyte activation or stimulation refers to an in vitro correlate of a process that regularly occurs when antigen interacts with specifically sensitized lymphocytes in the host. This technique is commonly used to assess cellular immunity in patients with immunodeficiency, autoimmunity, infectious diseases, and cancer. Lymphocyte activation measures the functional capability of T and B lymphocytes to proliferate following antigenic challenge and is therefore a more direct test of immunocompetence than merely enumerating types of lymphocytes. 10 Current applications include evaluation of immunocompetence and mechanisms of tissue damage of autoimmune disease; detection of changes in cellular immunocompetence in HIV and other infections that may be of prognostic value; determinations of origin of malignant lymphocytes; and monitoring of cellular changes following organ transplantation. 10

There are certain drugs and infectious diseases, namely, tuberculosis, that can result in a decrease in the CD4+ lymphocyte cell count in HIV negative subjects, 11–13 but all of these causes were excluded. Diabetes has been clinically associated with increased susceptibility to infection, but the specific mechanisms are multifactorial. At high blood glucose concentrations (high osmolarity) and during ketoacidosis, phagocytic and bactericidal activity is reduced. 10,13

No descriptions of PCP associated with transitory decreases in lymphocyte function, or PCP associated with diabetes were found in the literature.

The fact that the patient is clinically well after 8 months of follow-up, with controlled blood sugar levels, and that there is no clinical or laboratory evidence of any other disease, infectious or not, that could explain the transitory decrease in T lymphocyte function, raises the question whether persistently elevated blood glucose levels does not in some way affect T lymphocyte function.

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